Aminodihydrothiazine derivatives substituted with a cyclic group

ABSTRACT

This invention provides a compound of the formula (I): 
                         
wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R 1  is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl; R 2a  and R 2b  are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl; R 3a , R 3b , R 3c  and R 3d  are each independently hydrogen, halogen, hydroxy or optionally substituted lower alkyl etc.;
 
a pharmaceutically acceptable salt or solvate thereof,
 
which is useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.

TECHNICAL FIELD

This invention relates to a compound having an inhibitory activityagainst production of amyloid β protein and useful for treating diseasesinduced by production, secretion and/or deposition of amyloid β protein.

BACKGROUND ART

In the brain of Alzheimer's patient many insoluble spots (senile plaque)are found, which is formed by extraneuronal accumulation of a peptidecalled amyloid β protein comprised of about 40 amino acids. Neuronaldeath caused by the senile plaque is considered to develop Alzheimer'sDisease and an enhancer of amyloid β protein decomposition or vaccine ofamyloid β protein etc. are extensively studied as a remedy forAlzheimer's Disease.

Secretase is an enzyme producing amyloid β protein by intracellularcleavage of a protein called amyloid β protein precursor (APP). Anenzyme playing a role for producing an N-terminal of the amyloid βprotein is called BACE1 (beta-site APP-cleaving enzyme) and an inhibitorof the BACE1, which will reduce production of amyloid β protein, couldbe a remedy for treating Alzheimer's disease.

Patent literature 1 discloses a compound with a chemical structuresimilar to that of the compound of the present invention, having aninhibitory activity of NO synthetase and effective for treatingdementia.

Patent literature 2-5 and non-patent literature 1-2 disclose compoundswith a chemical structure similar to those of the compound of thepresent invention, and describe that each compound is useful as ananti-hypotensive agent, morphine-like analgesic or tranquilizer,intermediate of a therapeutic agent, NPYY5 antagonist, analgesic and thelike.

Patent literatures 6-14 disclose BACE-1 inhibitors having a chemicalstructure different from that of the compound of the present invention.Also, patent literature 15 discloses a BACE-1 inhibitor.

Patent literature 1: WO 96/014842 Pamphlet

Patent literature 2: U.S. Pat. No. 3,235,551

Patent literature 3: U.S. Pat. No. 3,227,713

Patent literature 4: JP H09-067355

Patent literature 5: WO 2005/111031 Pamphlet

Patent literature 6: WO 02/96897 Pamphlet

Patent literature 7: WO 04/043916 Pamphlet

Patent literature 8: WO 2005/058311 Pamphlet

Patent literature 9: WO 2005/097767 Pamphlet

Patent literature 10: WO 2006/041404 Pamphlet

Patent literature 11: WO 2006/041405 Pamphlet

Patent literature 12: US 2007/0004786A

Patent literature 13: US 2007/0004730A

Patent literature 14: US 2007/27199A

Patent literature 15: WO 2007/049532 Pamphlet

Non-patent literature 1: Journal of Heterocyclic Chemistry, 14, 717-723(1977)

Non-patent literature 2: Journal of Organic Chemistry, 33(8), 3126-3132(1968).

DISCLOSURE OF INVENTION Problem to be Solved

This invention provides with a compound having an inhibitory activityagainst BACE-1 and useful for treating diseases induced by production,secretion and/or deposition of amyloid β protein.

Means to Solve the Problem

The present invention provides with

-   1) a compound of the formula (I):

wherein the ring A is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group,

R¹ is optionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted lower alkynyl, an optionally substitutedcarbocyclic group or an optionally substituted heterocyclic group,

R^(2a) and R^(2b) are each independently hydrogen, optionallysubstituted lower alkyl or optionally substituted acyl,

R^(3a), R^(3b), R^(3c) and R^(3d) are each independently hydrogen,halogen, hydroxy, optionally substituted lower alkyl, optionallysubstituted lower alkenyl, optionally substituted acyl, optionallysubstituted lower alkoxy, optionally substituted carbocyclyl loweralkyl, optionally substituted heterocyclyl lower alkyl, optionallysubstituted carbocyclyl lower alkoxy, optionally substitutedheterocyclyl lower alkoxy, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted aralkyloxy, optionallysubstituted heteroaralkyloxy, optionally substituted lower alkylthio,carboxy, optionally substituted lower alkoxycarbonyl, optionallysubstituted amino, optionally substituted carbamoyl, an optionallysubstituted carbocyclic group or an optionally substituted heterocyclicgroup, or R^(3a) and R^(3b) or R^(3c) and R^(3d) may form a carbocyclicring together with a linked carbon atom or may form oxo,

provided the following compounds i) and ii) are excluded;

-   i) a compound in which R^(2a) is hydrogen, R^(2b) is hydrogen,    acetyl or phenyl, R¹ is methyl, and the ring A is phenyl or    4-methoxyphenyl;-   ii) a compound in which R^(2a) is hydrogen, R^(2b) is hydrogen,    acetyl or phenyl, R¹ is ethyl and the ring A is 3,4-dimethoxyphenyl,    a pharmaceutically acceptable salt or solvate thereof;-   1′) a compound of the formula (I):

wherein the ring A is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group,

R¹ is optionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted lower alkynyl, an optionally substitutedcarbocyclic group or an optionally substituted heterocyclic group,

R^(2a) and R^(2b) are each independently hydrogen, optionallysubstituted lower alkyl or optionally substituted acyl,

R^(3a), R^(3b), R^(3c) and R^(3d) are each independently hydrogen,halogen, hydroxy, optionally substituted lower alkyl, optionallysubstituted lower alkenyl, optionally substituted acyl, optionallysubstituted lower alkoxy, optionally substituted lower alkylthio,carboxy, optionally substituted lower alkoxycarbonyl, optionallysubstituted amino, optionally substituted carbamoyl, an optionallysubstituted carbocyclic group or an optionally substituted heterocyclicgroup, or

R^(3a) and R^(3b) or R^(3c) and R^(3d) may form a carbocyclic ringtogether with a linked carbon atom, provided the following compounds i)and ii) are excluded:

-   i) a compound in which R^(2a) is hydrogen, R^(2b) is hydrogen,    acetyl or phenyl, R¹ is methyl, and the ring A is phenyl or    4-methoxyphenyl;-   ii) a compound in which R^(2a) is hydrogen, R^(2b) is hydrogen,    acetyl or phenyl, R¹ is ethyl and the ring A is 3,4-dimethoxyphenyl,    a pharmaceutically acceptable salt or solvate thereof;-   2) the compound of 1) or 1′) described above,    wherein the ring A is

wherein the ring A′ is a carbocyclic group or a heterocyclic group,

-   G is

wherein R⁵ is hydrogen, lower alkyl or acyl,

-   R⁶ is optionally substituted lower alkyl, optionally substituted    lower alkenyl or optionally substituted lower alkynyl,-   W¹ is O or S,-   W² is O, S or NR⁵,-   Ak is optionally substituted lower alkylene, optionally substituted    lower alkenylene or optionally substituted lower alkynylene,-   the ring B is an optionally substituted carbocyclic group or an    optionally substituted heterocyclic group and each R⁵ may be    independent:-   R⁴ is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower    alkoxy, amino, lower alkylamino, acylamino or lower alkylthio and    each R⁴ may be independent;    A pharmaceutically acceptable salt or solvate thereof;-   2′) the compound of 1) or 1′) described above    wherein the ring A is

wherein the ring A′ is a carbocyclic group or a heterocyclic group,

-   G is

wherein R⁵ is hydrogen, lower alkyl or acyl,

-   R⁶ is optionally substituted lower alkyl, optionally substituted    lower alkenyl or optionally substituted lower alkynyl,-   W¹ is O or S,-   W² is O, S or NR⁵,-   Ak is optionally substituted lower alkylene, optionally substituted    lower alkenylene or optionally substituted lower alkynylene,-   the ring B is an optionally substituted carbocyclic group or an    optionally substituted heterocyclic group and each R⁵ may be    independent:-   R⁴ is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower    alkyl, lower alkoxy, amino, lower alkylamino, acylamino or lower    alkylthio and each R⁴ may be independent;    A pharmaceutically acceptable salt or solvate thereof;-   3) the compound of 2) or 2′) described above wherein the ring A′ is    phenyl or a nitrogen-containing aromatic heterocyclic group, a    pharmaceutically acceptable salt or solvate thereof;-   3′) the compound of 2) or 2′) described above wherein the ring A′ is    phenyl, a pharmaceutically acceptable salt or solvate thereof;-   3″) the compound of 2) or 2′) described above wherein the ring A′ is    a nitrogen-containing aromatic monocyclic hetercyclic group, a    pharmaceutically acceptable salt or solvate thereof;-   3′″) the compound of 2) or 2′) described above wherein the ring A′    is pyridyl, a pharmaceutically acceptable salt or solvate thereof;-   4) the compound of 1)-3), 1′), 2′), 3′), 3″) or 3″) described above    wherein R¹ is C1-C3 alkyl, a pharmaceutically acceptable salt or    solvate thereof;-   4′) the compound of 1)-3), 1′), 2′), 3′), 3″) or 3′″) described    above wherein R¹ is optionally substituted lower alkynyl, a    pharmaceutically acceptable salt or solvate thereof;-   5) the compound of 1)-4), 1′), 2′), 3′), 3″), 3′″) or 4′) described    above wherein R^(2a) and R^(2b) are both hydrogen, a    pharmaceutically acceptable salt or solvate thereof;-   6) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described    above wherein all of R^(3a), R^(3b), R^(3c) and R^(3d) are hydrogen,    a pharmaceutically acceptable salt or solvate thereof;-   6′) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described    above wherein R^(3a) and R^(3b) are the same substituent selected    from halogen and optionally substituted lower alkyl, a    pharmaceutically acceptable salt or solvate thereof;-   6″) the compound of 1)-5), 1′), 2′), 3′), 3′), 3′″) or 4′) described    above wherein R^(3c) and R^(3d) are the same substituent selected    from halogen and optionally substituted lower alkyl, a    pharmaceutically acceptable salt or solvate thereof;-   6′″) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′)    described above wherein R^(3a) and R^(3b) or R^(3c) and R^(3d) form    a carbocyclic ring together with a linked carbon atom a    pharmaceutically acceptable salt or solvate thereof;-   7) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described    above wherein R^(3c) or R^(3d) is optionally substituted carbocyclic    ring lower alkoxy or optionally substituted heterocyclyl lower    alkoxy, a pharmaceutically acceptable salt or solvate thereof;-   7′) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described    above wherein R^(3a) and R^(3b) form oxo together with a linked    carbon atom, a pharmaceutically acceptable salt or solvate thereof;-   8) a pharmaceutical composition comprising a compound of 1)-7), 1′),    2′), 3′), 3″), 3′″), 4′) 6′), 6″), 6′″) or 7′) described above, a    pharmaceutically acceptable salt or solvate thereof as an active    ingredient; and-   9) a pharmaceutical composition having a BACE 1 inhibitory activity    comprising a compound of 1)-7), 1′), 2′), 3′), 3″), 3′″), 4′) 6′),    6″), 6′″) or 7′) described above, a pharmaceutically acceptable salt    or solvate thereof as an active ingredient;

The present invention also provides with

-   10) the pharmaceutical composition having a BACE 1 inhibitory    activity of 9) described above, which is a composition having    inhibitory activity of amyloid β protein production;-   11) the pharmaceutical composition having a BACE 1 inhibitory    activity of 9) described above, which is a medicine for treating    diseases induced by production, secretion and/or deposition of    amyloid β protein;-   12) the pharmaceutical composition having a BACE 1 inhibitory    activity of 9) described above, which is a medicine for treating    Alzheimer's disease;-   13) a method for treating diseases induced by production, secretion    and/or deposition of amyloid β protein, characterized in    administering a compound of the formula (I) described in 1) above, a    pharmaceutically acceptable salt or solvate thereof;-   14) use of a compound of the formula (I) described in 1) above, a    pharmaceutically acceptable salt or solvate thereof described in 1)    above, in manufacturing a medicine for treating diseases induced by    production, secretion and/or deposition of amyloid β protein;-   15) a method for treating diseases induced by BACE 1 characterized    in administering a compound of the formula (I) described in 1)    above, a pharmaceutically acceptable salt or solvate thereof;-   16) use of a compound of the formula (I) described in 1) above, a    pharmaceutically acceptable salt or solvate thereof, in    manufacturing a medicine for treating diseases induced by BACE 1;-   17) a method for treating Alzheimer's disease characterized in    administering a compound of the formula (I) described in 1) above, a    pharmaceutically acceptable salt or solvate thereof; and-   18) use of a compound of the formula (I) described in 1) above, a    pharmaceutically acceptable salt or solvate thereof in manufacturing    a medicine for treating Alzheimer's disease.

Effect of Invention

A compound of the present invention is useful for treating diseasesinduced by production, secretion and/or deposition of amyloid β protein(Alzheimer's disease etc.).

BEST MODE FOR CARRYING OUT THE INVENTION

In this description, “halogen” includes fluorine, chlorine, bromine andiodine.

A moiety of halogen in “halogeno lower alkyl” and “halogeno loweralkoxycarbonyl” is the same as “halogen” above.

“Lower alkyl” includes C1-C15, preferably C1-C10, more preferably C1-C6and further more preferably C1-C3 straight or branched alkyl, and forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl,n-heptyl isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl areexemplified.

A moiety of alkyl in “lower alkoxy”, “halogeno lower alkyl”, “hydroxyllower alkyl”, “hydroxyl lower alkoxy”, “lower alkoxycarbonyl”, “halogenolower alkoxycarbonyl”, “lower alkoxycarbonyl lower alkyl”, “loweralkylamino”, “lower alkoxy lower alkyl”, “hydroxyimino lower alkyl”,“lower alkoxyimino lower alkyl”. “amino lower alkyl” “lower alkoxy loweralkoxy”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl loweralkenyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl loweralkynyl”, “lower alkyl carbamoyl”, “hydroxyl lower alkyl carbamoyl”,“lower alkoxyimino”, “lower alkylthio”, “lower alkylsulfonyl”, “loweralkylsulfonyloxy”, “lower alkyl sulfamoyl”, “lower alkyl sulfinyl”,“carbocyclyl lower alkyl”, “carbocyclyl lower alkyl”, “carbocyclyl loweralkoxy”, “carbocyclyl lower alkoxycarbonyl”, “carbocyclyl loweralkylamino”, “carbocyclyl lower alkyl carbamoyl”, “cycloalkyl loweralkyl”, “cycloalkyl lower alkoxy”, “cycloalkyl lower alkylamino”,“cycloalkyl lower alkoxycarbonyl”, “cycloalkyl lower alkylcarbamoyl”,“aryl lower alkyl”, “aryl lower alkoxy”, “aryl lower alkylamino”, “aryllower alkoxycarbonyl”, “aryl lower alkoxycarbamoyl”, “heterocyclyl loweralkyl”, “heterocyclyl lower alkoxy”, “heterocyclyl lower alkylamino”,“heterocyclyl lower alkoxycarbonyl” and “heterocyclyl loweralkylcarbamoyl” is the same as “alkyl” above.

“Optionally substituted lower alkyl” may be substituted with one or moreof substituent(s) selected from a substituent group α.

Group α is a group consisting of halogen, hydroxy, lower alkoxy, hydroxylower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, loweralkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxyimino,lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl,hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, loweralkylsulfonyl, cyano, nitro, a carbocyclic group and a heterocyclicgroup.

One or more of substituent(s) selected from the substituent group α isexemplified as a substituent of “optionally substituted lower alkoxy”,“optionally substituted lower alkoxycarbonyl” and “optionallysubstituted lower alkylthio”

“Lower alkylidene” includes a divalent group derived from the “loweralkyl” above, and methylidene, ethylidene, propylidene, isopropylidene,butylidene, pentylidene and hexylidene etc. are exemplified.

“Lower alkenyl” includes C2-C15, preferably C2-C10, more preferablyC2-C6 and further more preferably C2-C4 straight or branched alkenylhaving one or more double bond(s) at any position thereof. Examples oflower alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl,isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl,hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and thelike.

“Lower alkynyl” includes C2-C10, preferably C2-C8, more preferably C3-C6straight or branched alkynyl having one or more triple bond(s) at anyposition thereof. Examples of lower alkynyl include ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and thelike. Lower alkynyl may additionally have a double bond at any positionthereof.

One or more of substituent(s) selected from the substituent group α isexemplified as a substituent of “optionally substituted lower alkenyl”and “optionally substituted lower alkynyl”.

A moiety of lower alkenyl in “hydroxyl lower alkenyl”, “lower alkoxylower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “carbocyclyl loweralkenyl”, “lower alkenyloxy”, “lower alkenylthio” and “loweralkenylamino” is the same as that of “lower alkenyl”.

A moiety of lower alkynyl in “hydroxyl lower alkynyl”, “lower alkoxylower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “carbocyclyl loweralkynyl”, “lower alkynyloxy”, “lower alkenylamino” and “loweralkynylamino” is the same as that of “lower alkynyl” above.

One or more substituents selected from lower alkyl, acyl, hydroxyl,lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and aheterocyclic group etc. is exemplified as a substituent of “optionallysubstituted amino” and “optionally substituted carbamoyl”.

“Acyl” includes C1-C10 aliphatic acyl, carbocyclyl carbonyl andheterocyclic carbonyl, and examples of acyl include formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl,propioloyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl,pyridinecarbonyl, furancarbonyl, thiophenecarbonyl,benzotriazolecarbonyl, pyrazinecarbonyl, piperidinecarbonyl,thiomorpholino and the like.

A moiety of acyl in “acylamino” and “acyloxy” is the same as describedabove.

One or more substituents selected from the substituent group α isexemplified as a substituent in “optionally substituted acyl” and amoiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl isoptionally substituted with one or more substituent(s) selected fromlower alkyl, the substituent group α and lower alkyl substituted withone or more substituent(s) selected from the substituent group α.

“A carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, andnon-aromatic fused carbocyclic group etc.

“Cycloalkyl” includes C3-C10, preferably C3-C8 and more preferably C4-C8carbocyclic group and examples of cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl and the like.

A moiety of cycloalkyl in “cycloalkyl lower alkyl”, “cycloalkyloxy”,“cycloalkyl lower alkoxy”, “cycloalkylthio”, “cycloalkylamino”,“cycloalkyl lower alkylamino”, “cycloalkylsulfamoyl”,“cycloalkylsulfonyl”, “cycloalkylcarbamoyl”, “cycloalkyl loweralkylcarbamoyl”, “cycloalkyl lower alkoxycarbonyl” and“cycloalkylcarbonyl” is the same as “cycloalkyl” described above

“Cycloalkenyl” includes the above cycloalkyl having one or more doublebond(s) at any position on the ring, and examples of the cycloalkenylinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctynyl, and cyclohexadienyl etc.

Examples of “aryl” include phenyl, naphthyl, anthryl and phenanthryletc. and especially phenyl is preferable.

“Non-aromatic fused carbocyclic group” includes a group in which two ormore cyclic groups selected from “cycloalkyl”, “cycloalkenyl” and “aryl”described above fused, and examples of “Non-aromatic fused carbocyclicgroup” include indanyl, indenyl, tetrahydronaphthyl and fluorenyl etc.

“Forming a carbocyclic ring together with a linked carbon atom” meansthat two substituents jointly form “cycloalkyl” above.

A moiety of the carbocyclic ring in “carbocyclyloxy”, “carbocyclyl loweralkyl”, “carbocyclyl lower alkenyl”, “carbocyclyl lower alkynyl”,“carbocyclyl lower alkoxy”, “carbocyclyl lower alkoxycarbonyl”,“carbocyclylthio”, “carbocyclyl amino”, “carbocyclyl lower alkylamino”,“carbocyclylcarbonyl”, “carbocyclylsulfonyl”, “carbocyclylsulfonyl”,“carbocyclylcarbamoyl”, “carbocyclyl lower alkyl carbamoyl”,“carbocyclyloxycarbonyl” is the same as the “carbocyclic group”.

A moiety of aryl in “aryl lower alkyl”, “aryloxy”, “aryloxycarbonyl”,“aryloxycarbonyloxy”, “aryl lower alkoxycarbonyl”, “arylthio”,“arylamino”, “aryl lower alkoxy”, “aryl lower alkylamino”,“arylsulfonyl”, “arylsulfonyloxy”, “arylsulfinyl”, “arylsulfamoyl”,“arylcarbamoyl” and “aryl lower alkylcarbamoyl” is the same as the“aryl” above.

“Heterocyclic group” includes a heterocyclic group containing one ormore heteroatom(s) each independently selected from O, S and N, andexamples of “heterocyclic group” include 5- or 6-membered heteroarylsuch as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl andthiadiazolyl etc.; a non-aromatic heterocyclic group such as dioxanyl,thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl,thiazolidinyl, pyrrolidinyl, pyrrolinyl, inmidazolidinyl, imidazolinyl,pyrazolidinyl, pirazolinyl, piperidyl, piperazinyl, morpholinyl,moipholino, thiomorpholinyl, thiomorpholino, dihydropyridyl,tetrahydropyridyl, tetrahydrofinyl, tetrahydropyranyl, dihydrothiazolyl,tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl,hexahydroazepinyl, tetrahydrodiazepinyl and tetrahydropyridazinyl etc.;

a fused bicyclic heterocyclic group such as indolyl, isoindolyl,indazolyl, indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl,cinnolinyl, phthaladinyl, quinazolinyl, naphthilidinyl, quinoxalinyl,purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl,benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl,thienopyrazolyl, thienopyrazinyl, furopynolyl, thienothienyl,imidazopyridyl pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl,pyrazolotriazinyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl,naphthilidinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl,dihydrobenzinmidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl,benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl,dihydrobenzodioxinyl, dihydrobenzooxedinyl, dihydrobenzooxepinyl anddihydrothienodioxinyl etc.; and a fused tricyclic heterocyclic groupsuch as carbazolyl, acridinyl, xanthenyl, phenothiazinyl,phenoxathiinyl, phenoxadinyl, dibenzofuryl, imidazoquinolyl andtetrahydrocarbazolyl etc.; and preferably includes 5- or 6-memberedheteroaryl and a non-aromatic heterocyclic group.

A moiety of the heterocyclic group in “heterocyclyl lower alkyl”,“heterocyclyloxy”, “heterocyclylthio”, “heterocyclylcarbonyl”,“heterocyclyl lower alkoxy”, “heterocyclyl amino”, “heterocyclylcarbonylamino”, “heterocyclyl sulfamoyl”, “heterocyclylsulfonyl”,“heterocyclylcarbamoyl”, “heterocyclyloxycarbonyl”, “heterocyclyl loweralkylamino”, “heterocyclyl lower alkoxycarbonyl” and “heterocyclyl loweralkylcarbamoyl” is the same as the “heterocyclic group” above.

“A nitrogen-containing aromatic heterocyclic group” means a group of the“heterocyclic group” above containing at least one nitrogen atom, andexamples of the “nitrogen-containing aromatic heterocyclic group”include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl,pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl,triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl,thiazolyl and thiadiazolyl etc.;

-   a fused bicyclic heterocyclo group such as indolyl, isoindolyl,    indazolyl, indolidinyl, indolinyl, isoindolinyl, quinolyl,    isoquinolyl, cinnolinyl, phthaladinyl, quinazolinyl, naphthilidinyl,    quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl,    benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl,    benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl,    benzotriazolyl, imidazopyridyl, pyrazolopyridine, triazolopyridyl,    imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl,    isoquinolyl, naphthylidinyl, dihydrobenzofuryl, tetrahydroquinolyl,    tetrahydroisoquinolyl, dihydrobenzoxazine etc.; and-   a fused tricyclic heterocyclo group such as carbazolyl, acridinyl,    xanthenyl and imidazoquinolyl etc.; and pyrrolidinyl, pyrrolinyl,    imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,    piperazinyl, morpholinyl, morpholino, thiomorpholinyl,    thiomorpholino, dihydropiridyl, dihydrobenzimidazolyl,    tetrahydropyridyl, tetrahydrothiazolyl and tetrahydroisothiazolyl    etc.

“The heterocyclic group” or “nitrogen-containing aromatic heterocyclicgroup” above may be linked to other group at any position on the ring.

“Nitrogen-containing aromatic monocyclic heterocyclic group” means amonocyclic group in the “nitrogen-containing aromatic heterocyclicgroup” and examples of the “Nitrogen-containing aromatic monocyclicheterocyclic group” include 5- or 6-membered heteroaryl such aspyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.

“The nitrogen-containing aromatic monocyclic heterocyclic group” abovemay be linked to other group at any carbon atom on the ring.

Examples of a substituent in the “optionally substituted carbocyclicgroup” and “optionally substituted heterocyclic group” of the ring A andB include the substituent group α (preferably halogen, hydroxyl, acyl,acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, cyano, loweralkylamino, lower alkylthio etc.); lower alkyl optionally substitutedwith one or more substituent(s) selected from the substituent group α,hydroxyimino and lower alkoxyimino, wherein examples of preferablesubstituents include halogen, hydroxyl, lower alkoxy, loweralkoxycarbonyl etc.; amino lower alkyl substituted with one or moresubstituent(s) selected from the substituent group α, wherein examplesof preferable substituents include acyl, lower alkyl and/or lower alkoxyetc.;

-   hydroxyimino lower alkyl, lower alkoxyimino lower alkyl;-   lower alkenyl optionally substituted with one or more substituent(s)    selected from the substituent group α, wherein examples of    preferable substituents include lower alkoxycarbonyl, halogen and/or    halogeno lower alkoxycarbonyl;-   lower alkynyl optionally substituted with one or more substituent(s)    selected from the substituent group α, wherein examples of    preferable substituents include lower alkoxycarbonyl etc;-   lower alkoxy optionally substituted with one or more substituent(s)    selected from the substituent group α, wherein examples of    preferable substituents include halogenocarbamoyl, oxetane, lower    alkylcarbamoyl, hydroxyl lower alkylcarbamoyl;-   lower alkoxy lower alkoxy optionally substituted with one or more    substituent(s) selected from the substituent group α;-   lower alkenyloxy optionally substituted with one or more    substituent(s) selected from the substituent group α wherein    examples of preferable substituents include halogen, hydroxyl,    amino, lower alkyl etc.;-   lower alkoxy lower alkenyloxy optionally substituted with one or    more substituent(s) selected from the substituent group α;-   lower alkynyloxy optionally substituted with one or more    substituent(s) selected from the substituent group α, wherein    examples of preferable substituents include halogen, hydroxyl etc.;-   lower alkoxy lower alkynyloxy optionally substituted with one or    more substituent(s) selected from the substituent group α;-   lower alkylthio optionally substituted with one or more    substituent(s) selected from the substituent group α;-   lower alkenylthio optionally substituted with one or more    substituent(s) selected from the substituent group α;-   lower alkynylthio optionally substituted with one or more    substituent(s) selected from the substituent group α;-   lower alkylamino substituted with one or more substituent(s)    selected from the substituent group α;-   lower alkenylamino substituted with one or more substituent(s)    selected from the substituent group α;-   lower alkynylamino substituted with one or more substituent(s)    selected from the substituent group α;-   aminooxy optionally substituted with one or more substituent(s)    selected from lower alkylidene and the substituent group α;-   acyl substituted with one or more substituent(s) selected from the    substituent group α;-   lower alkylsulfonyl optionally substituted with one or more    substituent(s) selected from the substituent group α;-   lower alkylsulfinyl optionally substituted with one or more    substituent(s) selected from the substituent group α;-   sulfamoyl;-   lower alkylsulfamoyl optionally substituted with one or more    substituent(s) selected from the substituent group α;-   a carbocyclic group (preferably cycloalkyl, aryl etc.) optionally    substituted with one or more substituent(s) selected from the    substituent group α, azide, lower alkyl and halogeno lower alkyl;-   a heterocyclic group optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclyl lower alkyl (preferably cycloalkyl lower alkyl, aryl    lower alkyl etc.) optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   heterocyclyl lower alkyl optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclyloxy (preferably cycloalkyloxy, aryloxy etc.) optionally    substituted with one or more substituent(s) selected from the    substituent group α, azide, lower alkyl and halogeno lower alkyl;-   heterocyclyloxy optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclyl lower alkoxy (preferably cycloalkyl lower alkoxy, aryl    lower alkoxy, etc.) optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   heterocyclyl lower alkoxy (preferably cycloalkyl lower    alkoxycarbonyl, aryl lower alkoxycarbonyl etc.) optionally    substituted with one or more substituent(s) selected from the    substituent group α, azide, lower alkyl and halogeno lower alkyl,-   carbocyclyl lower alkoxycarbonyl optionally substituted with one or    more substituent(s) selected from the substituent group α, azide,    lower alkyl and halogeno lower alkyl;-   heterocyclyl lower alkoxycarbonyl optionally substituted with one or    more substituent(s) selected from the substituent group α, azide,    lower alkyl and halogeno lower alkyl;-   carbocyclylthio (preferably cycloalkylthio, arylthio etc.)    optionally substituted with one or more substituent(s) selected from    the substituent group α, azide, lower alkyl and halogeno lower    alkyl;-   heterocyclylthio optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclyl amino (preferably cycloalkylamino, arylamino etc.)    optionally substituted with one or more substituent(s) selected from    the substituent group α, azide, lower alkyl and halogeno lower    alkyl;-   heterocyclyl amino optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclyl lower alkylamino (preferably cycloalkyl lower    alkylamino, aryl lower alkylamino etc.) optionally substituted with    one or more substituent(s) selected from the substituent group α,    azide, lower alkyl and halogeno lower alkyl;-   heterocyclyl lower alkylamino optionally substituted with one or    more substituent(s) selected from the substituent group α, azide,    lower alkyl and halogeno lower alkyl;-   lower alkylsulfamoyl optionally substituted with one or more    substituent(s) selected from the substituent group α;-   carbocyclylsulfamoyl (preferably cycloalkyl sulfamoyl, arylsulfamoyl    etc.) optionally substituted with one or more substituent(s)    selected from the substituent group α, azide, lower alkyl and    halogeno lower alkyl;-   heterocyclylsulfamoyl optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclysulfonyl (preferably cycloalkyl sulfonyl, arylsulfonyl    etc.) optionally substituted with one or more substituent(s)    selected from the substituent group α, azide, lower alkyl and    halogeno lower alkyl;-   heterocyclylsulfonyl optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclylcarbamoyl (preferably cycloalkyl carbamoyl, aryl    carbamoyl etc.) optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   heterocyclyl carbamoyl optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   carbocyclyl lower alkylcarbamoyl (preferably cycloalkyl lower    alkylcarbamoyl, aryl lower alkylcarbamoyl etc.) optionally    substituted with one or more substituent(s) selected from the    substituent group α, azide, lower alkyl and halogeno lower alkyl;-   heterocyclyl lower alkylcarbamoyl optionally substituted with one or    more substituent(s) selected from the substituent group α, azide,    lower alkyl and halogeno lower alkyl, carbocyclyloxycarbonyl    (preferably cycloalkyloxycarbonyl, aryloxycarbonyl etc.) optionally    substituted with one or more substituent(s) selected from the    substituent group α, azide, lower alkyl and halogeno lower alkyl;-   heterocyclyloxycarbonyl optionally substituted with one or more    substituent(s) selected from the substituent group α, azide, lower    alkyl and halogeno lower alkyl;-   lower alkylenedioxy optionally substituted with halogen;-   oxo, azide and the like.    These may be substituted with one or more substituents selected from    these groups.

Also the ring A may be substituted with one or more group(s) selectedfrom

wherein Ak¹, Ak² and Ak³ are each independently a single bond,optionally substituted lower alkylene, optionally substituted loweralkenylene or optionally substituted lower alkynylene;

-   Ak⁴ is optionally substituted lower alkylene, optionally substituted    lower alkenylene or optionally substituted lower alkynylene;-   W¹ and W³ are each independently O or S,-   W² is O, S or NR⁵,-   R⁵ and R⁶ are each independently hydrogen, lower alkyl, hydroxy    lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower    alkyl, carbocyclyl lower alkyl, lower alkenyl, hydroxyl lower    alkenyl, lower alkoxy lower alkenyl, lower alkoxycarbonyl lower    alkenyl, carbocyclyl lower alkenyl, lower alkynyl, hydroxyl lower    alkynyl, lower alkoxy lower alkynyl, lower alkoxycarbonyl lower    alkynyl, carbocyclyl lower alkynyl or acyl;-   R⁷ is hydrogen or lower alkyl;-   the ring B is an optionally substituted carbocyclic group or an    optionally substituted heterocyclic group; and-   p is 1 or 2; W¹, W³ or W⁵ may be independent when it is pluralized.    Additionally the oxygen atom of (xii) may be cis or trans to the    substituent R⁷.

Preferable examples of (i) to (xixi) above include

wherein Ak is optionally substituted lower alkylene, optionallysubstituted lower alkenylene or optionally substituted lower alkynylene,and the other symbols are the same as described above.

In other cases of “an optionally substituted carbocyclic group” and “anoptionally substituted heterocyclic group”, one or more substituent(s)selected from a group of lower alkyl and the substituent group α may beexemplified as a substituent of “an optionally substituted carbocyclicgroup” and “an optionally substituted heterocyclic group”

“Heteroaryl” includes an aromatic cyclic group among the “heterocyclicgroup” above.

“Lower alkylene” includes C1-C10, preferably C1-C6, more preferablyC1-C3 straight or branched divalent carbon chain, and for example,methylene, dimethylene, trimethylene, tetramethylene and methyltrimethylene are exemplified.

A moiety of lower alkylene in “lower alkylenedioxy” is the same as the“lower alkylene” described above.

“Lower alkenylene” includes C2-C10, preferably C2-C6, more preferablyC2-C4 straight or branched divalent carbon chain having a double bond atany arbitrary position thereof, and vinylene, propenylene, butenylene,butadienylene, methyl propenylene, pentenylene and hexenylene areexemplified.

“Lower alkynylene” includes C2-C10, preferably C2-C6, more preferablyC2-C4 straight or branched divalent carbon chain having a triple bondand also a double bond at any arbitrary position thereof and forexample, ethynylene, propynylene, butynylene, pentynylene and hexynyleneare exemplified.

Examples of a substituent in “optionally substituted lower alkylene”,“optionally substituted lower alkenylene” and “optionally substitutedlower alkynylene” include the substituent group α, and preferablyhalogen and hydroxyl etc. are exemplified.

Examples of a substituent in “optionally substituted carbocyclyl loweralkyl”, “optionally substituted heterocyclyl lower alkyl”, “optionallysubstituted carbocyclyl lower alkoxy”, and “optionally substitutedheterocyclyl lower alkoxy” include one or more substituent(s) selectedfrom lower alkyl and the substituent group α.

In this specification, “solvate” includes a solvate with an organicsolvent and a hydrate etc. and hydrate may be coordinated with optionalnumber of water molecule.

The compound (I) includes pharmaceutical acceptable salt thereof.Examples of the pharmaceutical acceptable salt include a salt with analkali metal such as lithium, sodium and potassium etc., an alkali earthmetal such as magnesium, calcium etc., ammonium, an organic base and anamino acid; a salt with an inorganic acid such as hydrochloric acid,sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid orhydroiodic acid etc., and an organic acid such as acetic acid,trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalicacid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malicacid, benzoic acid, phthalic acid, benzenesulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.Especially hydrochloric acid, phosphoric acid, tartaric acid or methanesulfonic acid is preferable. These salts can be prepared by a methodusually carried out.

The compound (I) is not construed to be limited to a specific isomer butto include all possible isomers such as a keto-enol isomer, animine-enamine isomer, a diastereoisomer, an optical isomer and arotational isomer etc. For example, a compound (I) in which R^(2a) ishydrogen includes a tautomer as follows;

The compound (I) of the present invention can be prepared, for example,according to the non-patent literature 1 or a method described below;

Preparation of an Aminodihydrothiazine Ring (I-1) or (I-2):

(In the scheme above, at least one of R^(2b) and R^(2c) is hydrogen,R^(3b) and R^(3d) are each independently hydrogen, halogen, hydroxyl,optionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted acyl, optionally substituted loweralkoxy, optionally substituted lower alkylthio, carboxy, optionallysubstituted lower alkoxycarbonyl, optionally substituted amino,optionally substituted carbamoyl, an optionally substituted carbocyclicgroup, or an optionally substituted heterocyclic group, and the othersymbols are the same as described above.)

-   The 1^(st) step: A Grignard reagent having a corresponding    substituent of the objective compound such as vinyl magnesium    chloride, vinyl magnesium bromide and propenyl magnesium bromide    etc. is added to a compound a which is commercially available or can    be prepared by a known method, in a solvent such as ether,    tetrahydrofuran etc. or a mixed solvent of ether-tetrahydrofuran    etc., at −100° C. to 50° C., preferably −80° C. to 0° C. and the    mixture is stirred for 0.2 to 24 hours, preferably 0.2 to 5 hours to    give a compound b.-   The 2^(nd) step: To a compound b in an acid such as acetic acid,    trifluoroacetic acid, hydrochloric acid, sulfuric acid etc. or a    mixture thereof under the presence of a solvent such as toluene etc.    or without a solvent, is added a substituted thiourea having a    corresponding substituent of the objective compound such as    thiourea, N-methylthiourea, N,N′-dimethylthiourea etc., and the    mixture is stirred at −20° C. to 100° C., preferably 0° C. to 80° C.    for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a    compound c.-   The 3^(rd) step: To a compound c in a solvent such as toluene etc.    or without a solvent, is added an acid such as trifluoroacetic acid,    methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid    etc. or a mixture thereof and reacted at −20° C. to 100° C.,    preferably 0° C. to 50° C. for 0.5 hours to 120 hours, preferably 1    hour to 72 hours to give a compound (I-2) when R^(2b) is hydrogen or    a compound (I-1) when R^(2c) is hydrogen.    Preparation of an Aminodihydrothiazine Ring (I-3):

(In the scheme above. L is a leaving group such as halogen or loweralkylsulfonyl etc. and the other symbols are the same as describedabove.)

-   The 1^(st) step: Thiocyanate such as sodium thiocyanate or ammonium    thiocyanate etc. is reacted with a compound d, which is commercially    available or can be prepared by a known method, in a solvent such as    toluene, chloroform, tetrahydrofuran etc. under the presence of    water and an acid such as hydrochloric acid or sulfuric acid etc. at    0° C. to 150° C., preferably at 20° C. to 100° C. for 0.5 to 24    hours, preferably 1 to 12 hours to give a compound e.-   The 2^(nd) step: A reducing agent such as sodium borohydride etc. is    added to and reacted with a compound e in a solvent such as    tetrahydrofuran, methanol, ethanol, water etc. or a mixture of    ethanol-water etc. under the presence of buffering agent such as    sodium dihydrogen phosphate at −80° C. to 50° C., preferably at    −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours to    give a compound f.-   The 3^(rd) step: A compound f is reacted with a halogenating agent    such as thionyl chloride, phosphoryl chloride, carbon    tetrachloride-triphenylphosphine etc. in a solvent such as toluene,    dichloromethane etc. or without a solvent at −80° C. to 50° C.,    preferably at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5    to 12 hours; or it is reacted with a sulfonating agent such as    methanesulfonyl chloride, p-toluenesulfonyl chloride etc. in a    solvent such as toluene, dichloromethane etc. under the presence of    a base such as triethylamine etc. at −80° C. to 50° C., preferably    at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours    to give a compound g.-   The 4^(th) step: A compound g is reacted with ammonia or a primary    amine such as methylamine etc. in a solvent such as methanol,    ethanol, water etc. or a mixture of methanol-water etc. at −20° C.    to 80° C., preferably at 0° C. to 40° C. for 0.5 to 48 hours,    preferably 1 to 24 hours to give the compound (I-3).    Preparation of an Aminodihydrothiazine Ring (I-6) or an    Aminotetrahydrothiazine Ring (I-7)

(In the scheme above, at least one of R^(2b) and R^(2c) is hydrogen andthe other symbols are the same as described above.)

-   The 1^(st) step: Thiourea or a substituted thiourea corresponding to    the objective compound such as N-methyl thiourea,    N,N-dimethylthiouers, N,N′-dimethylthiouera etc. is reacted with a    compound o, which is commercially available or can be prepared by a    known method, in a solvent such as ethanol, methanol,    tetrahydrofuran, toluene etc. at −20° C. to 200° C., preferably at    0° C. to 150° C. for 0.5 to 200 hours, preferably 1 to 120 hours to    give a compound p.-   The 2^(nd) step: A Grignard reagent corresponding to the objective    compound such as methyl magnesium chloride, ethyl magnesium bromide    and benzyl magnesium bromide etc. is added to a compound p in a    solvent such as ether, tetrahydrofuran etc. or a mixed solvent    thereof at −100° C. to 50° C., preferably −80° C. to 30° C. and the    mixture is stirred for 0.2 to 24 hours, preferably 0.5 to 5 hours to    give a compound q.-   The 3^(rd) step: To a compound q in a solvent such as toluene etc.    or without a solvent, is added an acid such as trifluoroacetic acid,    methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid    etc. or a mixture thereof and reacted at −20° C. to 100° C.,    preferably 0° C. to 50° C. for 0.5 hours to 200 hours, preferably 1    hour to 150 hours to give a compound (I-6) (R^(2c)═H) or a compound    (I-7) (R^(2b)═H).    Preparation of an Aminodihydrothiazine Ring (I-8)

(In the Scheme, Each Symbol is the Same as Described Above)

-   The 1^(st) step: Ammonium chloride is added to a compound r which    can be prepared by a known method in a solvent such as acetic acid    etc. at 0° C. to 200° C., preferably 10° C. to 100° C. for 0.1 hours    to 100 hours, preferably 0.5 hour to 24 hours to give a compound.-   The 2^(nd) step: A reducing agent such as lithium aluminum hydride,    diisobutyl aluminium hydride etc. is reacted with a compound s in a    solvent such as tetrahydrofuran, diethyl ether etc. at −80° C. to    150° C., preferably 0° C. to 100° C. for 0.1 hours to 24 hours,    preferably 0.5 hour to 12 hours to give a compound t.-   The 3^(rd) step: Isothiocyanate corresponding to the objective    compound such as 4-methoxybenzyl isothiocyanate, t-butyl    isothiocyanate etc. or carbamoyl halide corresponding to the    objective compound such as N,N-dimethyl thiocarbamoyl chloride,    N,N-diethyl thiocarbamoyl chloride etc. is reacted with a compound t    in a solvent such as toluene, chloroform, tetrahydrofuran etc. under    the presence of a base such as diisopropylethylamine, triethylamine,    pyridine, sodium hydroxide etc. or without a base at 0° C. to 150°    C., preferably 20° C. to 100° C. for 0.5 hours to 120 hours,    preferably 1 hour to 72 hours to give a compound u.-   The 4^(th) step: A halogenating agent such as thionyl chloride,    phosphoryl oxychloride, carbon tetrachloride-triphenyl phosphine    etc. is reacted with a compound u in a solvent such as acetonitrile,    toluene, dichloromethane etc. at −80° C. to 50° C., preferably    −20° C. to 20° C. for 0.1 hours to 24 hours, preferably 0.5 hour to    12 hours, or a sulfonylating agent such as methanesulfonyl chloride,    p-toluenesulfonyl chloride is reacted with a compound u in a solvent    such as toluene, dichloromethane etc. under the presence of a base    such as triethylamine at −80° C. to 50° C., preferably −20° C. to    20° C. for 0.1 hours to 24 hours, preferably 0.5 hour to 12 hours.    The resulting halogenated compound or sulfonate ester derivative is    reacted with a base such as diisopropylethylamine, potassium    carbonate, sodium bicarbonate, sodium hydride, sodium hydroxide etc.    at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 hours to    120 hours, preferably 1 hour to 72 hours to give a compound (I-8).    Preparation of an Acylamino Derivative (I-13) and/or (I-14)

(In the scheme, R¹⁷ is optionally substituted lower alkyl, an optionallysubstituted carbocyclic group or an optionally substituted heterocyclicgroup and other symbols are the same as described above)

An acylating agent corresponding to the objective compound such asbenzoyl chloride, 2-furoyl chloride, acetic anhydride etc. is reactedwith a compound (I-12) in which R^(2b) is hydrogen under the presence ofa solvent such as tetrahydrofuran, dichloromethane etc. or without asolvent and under the presence of a base such as pyridine ortriethylamine etc. or without a solvent at −80° C. to 100° C.,preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1hour to 12 hours, or a compound (I-12) is reacted with a carboxylic acidhaving a substituent corresponding to the objective compound such asamino acid or glycolic acid etc. in a solvent such as dimethylformamide,tetrahydrofuran, dichloromethane etc. under the presence of acondensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazoleetc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hoursto 24 hours, preferably 1 hour to 12 hours to give a compound (I-13)and/or (I-14)(when R^(2a) is hydrogen).

Preparation of a Carbamoyl Derivative (I-17)

(In the scheme above, CONR¹⁸R¹⁹ is optionally substituted carbamoyl andthe other symbols are the same as described above)

A compound (I-16) having a carboxyl group as a substituent on the ring Ais reacted with a primary or secondary amine having a substituentcorresponding to the objective compound (e.g., aniline, 2-aminopyridine,dimethylamine etc.) in a solvent such as dimethylformamide,tetrahydrofuran, dichloromethane etc. under the presence of acondensation agent such as dicyclohexylcarbodiimide,carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazoleetc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hoursto 24 hours, preferably 1 hour to 12 hours to give a compound (I-17).

Preparation of an Acylamino Derivative (I-19)

(In the scheme, NHR²⁰ is optionally substituted amino, NR²⁰COR²¹ isoptionally substituted acylamino, optionally substituted ureido orcarboxyamino having a substituent on the oxygen atom and the othersymbols are the same as described above.)

A compound (I-18) having an optionally substituted amino group on thering A is reacted with a reagent having a substituent corresponding tothe objective compound such as acid chlorides, acid anhydrides,chlorocarbonate esters, isocyanates etc. under the presence of a solventsuch as tetrahydrofuran, dichloromethane etc. or without a solvent underthe presence of a base such as pyridine, triethylamine etc. or without abase at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hoursto 24 hours, preferably 1 hour to 12 hours, or a compound (I-18) isreacted with a carboxylic acid having a substituent corresponding to theobjective compound such as benzoic acid, 2-pyridinecarboxylic acid etc.in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethaneetc. under the presence of a condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimide-N-hydroxybenzotriazole etc. at −80° C. to 100°C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1hour to 12 hours to give a compound (I-19).

Preparation of an Alkylamino Derivative (I-20)

(In the Scheme, NHR² is optionally substituted amino and R²² is loweralkyl.)

A compound (I-18) having an amino group on the ring A is reacted with analdehyde having a substituent corresponding to the objective compoundsuch as benzaldehyde, pyridine-2-carboxaldehyde etc. and a reducingagent such as sodium cyanoborohydride, sodium triacetoxyborohydride etc.in a solvent such as dichloromethane, tetrahydrofuran etc. under thepresence of an acid such as acetic acid etc. or without an acid at −80°C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours,preferably 1 hour to 24 hours to give a compound (I-20).

Preparation of a Substituted Alkoxy Derivative (I-22).

(In the scheme above, R²³ is optionally substituted lower alkyl, anoptionally substituted carbocyclic group or an optionally substitutedheterocyclic group and the other symbols are the same as describedabove.)

A compound (I-21) having a hydroxy group on the ring A is reacted withan alkylating agent having a substituent corresponding to the objectivecompound such as benzyl chloride, methyl iodide etc. in a solvent suchas dimethylformamide, tetrahydrofuran etc. under the presence of a basesuch as potassium carbonate, sodium hydroxide, sodium hydride etc. at−80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150hours, preferably 1 hour to 24 hours, or a compound (I-18) is reactedwith an alcohol such as 2-aminoethanol etc. in a solvent such asdimethylformamide, tetrahydrofuran etc. under the presence of aMitsunobu reagent such as triphenylphosphine-azodicarboxylic aciddiethyl ester etc. at −80° C. to 100° C., preferably 0° C. to 40° C. for0.5 hours to 72 hours, preferably 1 hour to 24 hours to give a compound(I-22).

Introduction of a Substituent by Palladium Coupling

(In the scheme above, Hal is halogen, G is optionally substituted loweralkenyl, optionally substituted alkynyl, optionally substitutedalkoxycarbonyl, an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group etc. and the other symbols arethe same as described above.)

A compound (I-23) having halogen as a substituent on the ring A isreacted with a compound having a substituent corresponding to theobjective compound (e.g., styrene, propargyl alcohol, aryl boronic acid,carbon monoxide etc.) in a solvent such as tetrahydrofuran,dimethylfomamide, 1,2-dimethoxyethane, methanol etc. under the presenceof a base such as triethylamine, sodium carbonate etc., a palladiumcatalyst such as palladium acetate, palladium chloride etc. and a ligandsuch as triphenylphosphine etc. and under irradiation of microwave orwithout the irradiation, at −80° C. to 150° C., preferably 0° C. to 100°C. for 0.5 hours to 72 hours, preferably 1 hour to 24 hours to give acompound (I-24).

Preparation of an Oxime Derivative (I-26)

(In the scheme above. R²⁴ is hydrogen, optionally substituted loweralkyl etc., R²⁵ is hydrogen, optionally substituted lower alkyl,optionally substituted lower alkenyl, an optionally substitutedcarbocyclic group or an optionally substituted heterocyclic group etc.,and the other symbols are the same as described above.)

A compound (I-25) having an acyl group as a substituent of the ring A isreacted with a hydroxylamine having a substituent corresponding to theobjective compound such as hydroxylamine, methoxylamine,O-benzylhydroxylamine etc. or a salt thereof in a solvent such asmethanol, ethanol etc. under the presence of an additive such aspotassium acetate etc. or without an additive at −80° C. to 100° C.,preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hourto 72 hours to give a compound (I-26).

Coupling Reaction

(In the scheme above, R²⁶ is a substituent corresponding to eachobjective compound)The 1^(st) Step:

A compound v is reacted with a reagent having a substituentcorresponding to the objective compound such as acyl halide, acidanhydride, chlorocarbonate ester, isocyanate etc. (e.g., benzoylchloride, 2-furoyl chloride, acetic anhydride, benzyl chloroformate,di-tert-butyl dicarbonate, phenyl isocyanate etc.) in a solvent such astetrahydrofuran, dichloromethane, dimethylfomamide etc. or without asolvent under the presence of a base such as pyridine, triethylamineetc. or without a base at −80° C. to 100° C., preferably −20° C. to 40°C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or acompound A is reacted with a carboxylic acid having a substituentcorresponding to the objective compound such as benzoic acid,2-pyridinecarboxylic acid etc. in a solvent such as dimethylformamide,tetrahydrofuran, dichloromethane, methanol etc. under the presence of acondensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride,2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate etc. at −80° C. to 100° C., preferably −20° C. to40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to givea compound w.

When the substituent R has a functional group which disturb the saidreaction, it can be carried out by protecting the functional group witha suitable protecting group and then deprotecting it at a subsequentappropriate step.

The 2^(nd) Step:

A compound w is reacted in a solvent such as methanol, ethanol, ether,tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate etc.containing trifluoroacetic acid etc. or in neat, or in neattrifluoroacetic acid at −30° C. to 100° C., preferably 0° C. to 90° C.for 0.5 to 12 hours to give a compound (I-27). Alternatively, theobjective compound can be synthesized according to the method describedin Protective Groups in Organic Synthesis, Theodora W Green (John Wiley& Sons) etc.

Preparation of an Optically Active Isomer

1) Preparation of an Optically Active Isomer ae

For example, an optically active isomer ae, one embodiment of thecompounds of the present invention, can be prepared according to thefollowing scheme:

(In the scheme above, R¹ is optionally substituted lower alkyl,optionally substituted lower alkenyl or optionally substituted loweralkynyl; R²⁷ is a chiral sulfoxide having optionally substituted loweralkyl, optionally substituted lower alkenyl, an optionally substitutedcarbocyclic group or an optionally substituted heterocyclic group, or achiral auxiliary group such as α-methyl benzyl etc.; R^(3a), R^(3b),R^(3c) and R^(3d) are each independently hydrogen, halogen, hydroxyl,optionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted acyl, carboxy, optionally substitutedlower alkoxycarbonyl, optionally substituted amino, optionallysubstituted carbamoyl, an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; R²⁸ is optionally substitutedlower alkyl or optionally substituted lower alkenyl; R^(2a) and R^(2b)are each independently hydrogen, optionally substituted lower alkyl oroptionally substituted acyl; and the other symbols are the same asdescribed above.)

The compounds y and z above can be prepared by a method described in

-   (1) T. Fujisawa et al., Tetrahedron Lett., 37, 3881-3884 (1996),-   (2) D. H. Hua et al, Sulfur Reports, vol. 21, pp. 211-239 (1999)-   (3) Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), or-   (4) T. Vilavan et al, Current Organic Chemistry, 9, 1315-1392    (2005).

Alternatively, these compounds can be prepared by optical resolution ofeach intermediate or the final product, or according to methodsdescribed below. Examples of the optical resolution method include aseparation of optical isomers using an optically active column, kineticresolution by an enzyme reaction etc., crystallization of diastereomersby salt formulation using a chiral acid or chiral base, and apreferential crystallization etc.

-   The 1^(st) step: Compound y can be obtained by reacting Compound x,    which is commercially available or can be prepared by a known    method, with a chiral reagent having a substituent corresponding to    the objective compound such as α-methylbenzylamine, para-toluene,    tert-butylsulfine amide etc. at 60° C. to 120° C., preferably 80° C.    to 100° C. in a solvent such as ether, tetrahydrofuran, toluene,    benzene etc. or a mixed solvent such as ether-tetrahydrofuran etc.    for 0.5 to 24 hours, preferably 0.5 to 5 hours, in the presence of    molecular sieves or magnesium sulfate etc., under continuous    evaporation by Dean-Stark apparatus, or according to the method    described in the above literatures.-   The 2^(nd) step: A compound z can be diastereo-selectively obtained    by reacting an enolate of lithium, aluminum, zinc, titan etc.    prepared form a reagent having a substituent corresponding to the    objective compound such as acetate ester etc., which is commercially    available or can be prepared by a known method, or ketenesilyl    acetate prepared from a reagent having a substituent corresponding    to the objective compound such as ethyl acetate etc. with a compound    a in a solvent such as ether, tetrahydrofuran, toluene,    dichloromethane etc. or a mixed solvent such as    ether-tetrahydrofuran etc. under the presence of a Lewis acid such    as titanium tetrachloride, ether-trifluoroborane complex etc. or    without a Lewis acid at −100° C. to 50° C., preferably −80° C. to    −30° C. for 0.5 to 24 hours, preferably 0.5 to 5 hours.    Alternatively, the compound z can be diastereo-selectively prepared    by the method described in the literature (1) or (3).-   The 3^(rd) step: A compound z is reacted with a compound c in a    solvent such as methanol, ethanol, ether, tetrahydrofuran,    1,4-dioxane, dichloromethane, ethyl acetate etc. containing hydrogen    chloride, trifluoroacetic acid etc. or in neat trifluoroacetic acid    at −30° C. to 100° C., preferably −10° C. to 90° C. for 0.5 to 12    hours, preferably 0.5 to 5 hours to give a compound aa.-   The 4^(th) step: A reducing agent such as borane-tetrahydrofuran    complex, borane-dimethyl sulfoxide complex, borane-triethylamine    complex, borane-pyridine complex etc. or ether- or    tetrahydrofuran-solution thereof is reacted with a compound aa in a    solvent such as ether, tetrahydrofuran, toluene etc. or a mixed    solvent such as ether-tetrahydrofuran etc. at −30° C. to 30° C.,    preferably −10° C. to 20° C. for 0.5 to 12 hours, preferably 0.5 to    5 hours to give a compound ab.-   The 5^(th) step: Calcium carbonate or potassium carbonate etc. is    added to a compound ab in a solvent such as dichloromethane, toluene    etc. or a mixed solvent such as dichloromethane-water etc. and    thiophosgene is added at −30° C. to 50° C., preferably −10° C. to    25° C. and the mixture is reacted for 0.5 to 12 hours, preferably    0.5 to 5 hours to give a compound ac.-   The 6^(th) step: Oxalyl chloride or thionyl chloride etc. and a    catalytic amount of N,N-dimethylformamide are added to a compound ac    in a solvent such as dichloromethane, tetrahydrofuran, toluene etc.    at −30° C. to 50° C., preferably −10° C. to 20° C. and the mixture    is reacted at 0° C. to 100° C., preferably 20° C. to 90° C. for 0.5    to 12 hours, preferably 0.5 to 5 hours to give a compound ad.    Alternatively, it is obtained by a method described in Comprehensive    Organic Transformations, Richard C Larock (McGraw-Hill).-   The 7^(th) step: 15% to 30% Ammonia water or a reagent having a    substituent corresponding to the objective compound such as    tert-butylamine etc. is added to a compound ad in a solvent such as    ethyl acetate, dichloromethane, tetrahydrofuran, toluene etc. at    −30° C. to 50° C., preferably −10° C. to 30° C. and the mixture is    reacted at −10° C. to 30° C., preferably 0° C. to 30° C. for 0.5 to    72 hours to give a compound ae-i or a compound ae-ii.

When R^(2a) and/or R^(2b) is hydrogen in the resulting compound ae-i orae-ii, a substituent of the objective compound, R² and/or RTh, may befurther introduced by a conventional method if it is necessary.

1′) Method for Preparing an Optically Active Isomer Method B

An optically active compound ah of the present invention can be alsoprepared by a method below:

(In the Scheme, the Symbols are the Same as Described Above.)

-   The 1^(st) step to the 4^(th) step: the same as described in 1)    above.-   The 5^(th) step: Isothiocyanate having a protecting group which is    commercially available or can be prepared by a known method is added    to a compound ab in a solvent such as dichloromethane, toluene,    acetone etc. or a mixed solvent at −30° C. to 50° C., preferably    −10° C. to 25° C. and the mixture is reacted for 0.5 to 12 hours,    preferably 0.5 to 5 hours to give a compound ag.-   The 6^(th) step: Oxalyl chloride or thionyl chloride etc. and a    catalytic amount of N,N-dimethylformamide are added to a compound ag    in a solvent such as dichloromethane, tetrahydrofuran, toluene etc.    at −30° C. to 50° C., preferably −10° C. to 25° C., or    1-chloro-N,N-2-trimethyl-1-propenenylamine is added to a compound    ag, and reacted at 0° C. to 100° C., preferably 20° C. to 90° C. for    0.5 to 72 hours to give a compound ah-i or ah-ii.    2) Introduction of R^(3a) and R^(3b)

An optically active compound ae-iii or ae-iv of the present inventioncan be also prepared by introducing R^(3a) and R^(3b) as shown below:

(In the Scheme Above, Each Symbol is the Same as Described Above)

When preparing a compound ae-iii or ae-iv in which R^(3a) and R aresubstituted on the carbon atom next to S atom, a compound z is processedthrough the 3^(rd) and 4^(th) steps in place of the 3^(rd) and 4^(th)steps of 1) described above, and R^(3a) and R^(3b) are introduced inadvance.

-   The 3^(rd) step: A Grignard reagent having a substituent    corresponding to the objective compound such as methyl magnesium    chloride, ethyl magnesium bromide etc. is added to a compound z in a    solvent such as ether, tetrahydrofuran etc. or a mixed solvent such    as ether-tetrahydrofuran etc. at −100° C. to 50° C., preferably    −80° C. to 30° C., or a compound z is converted to Weinreb Amide and    reacted with a Grignard reagent having a substituent corresponding    to the objective compound such as R^(3a)MgBr, R^(3b)MgBr. The    reaction mixture is reacted for 0.2 to 24 hours, preferably 0.2 to 5    hours to give a compound aa′.-   The 4^(th) step: A compound aa′ is reacted in a solvent such as    methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane,    dichloromethane, ethyl acetate etc. containing hydrogen chloride,    trifluoroacetic acid etc. or in neat trifluoroacetic acid at −30° C.    to 100° C., preferably −10° C. to 90° C. for 0.5 to 12 hours,    preferably 0.5 to 5 hours to give a compound ab′.

The compound ab′ is processed in the same reactions as the 5^(th) to7^(th) steps of 1) above to give the objective compound ae-iii or ae-iv.

When the substituent L of a compound ad′ is eliminated to give acompound ad″ shown below, the objective compound ae′-iii or ae′-iv isobtained by processing the compound ad′ it through the 7^(th) step inplace of the 7^(th) step described in 1) above.

-   The 7^(th) step: A compound ad″ is dissolved in conc. sulfuric acid,    trifluoroacetic acid, trifluoromethanesulfonic acid etc. and reacted    at −30° C. to 100° C., preferably −100° C. to 40° C. for 0.1 to 12    hours, preferably 0.5 to 5 hours to give a compound ae′.    3) Conversion of a Substituent (1)

A preparation of a compound af-1 by conversion of the substituent isillustrated below:

(In the scheme, R^(8a) and R^(ba) are an amino-protecting group, and theother symbols are the same as described above.)

Trisdibenzylideneacetonedipalladiunm, palladium acetate, palladium(0)prepared in situ etc. and a phosphine ligand such astri-tert-butylphosphine, dicyclohexylbiphenylphosphine etc. are added toa compound ae-1 in a solvent such as tetrahydrofuran, toluene, xyleneetc. and further a reagent having a substituent corresponding to theobjective compound such as lithium hexamethylenedisilazide,benzophenonimine etc. is added thereto at −10° C. to 30° C., then thereaction mixture is reacted at 30° C. to 120° C., preferably 50° C. to100° C. for 0.5 to 48 hours, preferably 3 to 20 hours to give a compoundaf-1.

Any amino-protecting group which is deprotected by a method described inProtective Groups in Organic Synthesis, Theodora W Green (John Wiley &Sons) etc. can be used and examples of the protecting group includelower alkoxycarbonyl, lower alkenyloxycarbonyl, trialkylsilyl, acyl,methanesulfonyl, trifluoromethanesulfonyl and toluenesulfonyl etc.

4) Conversion of a Substituent (2)

A preparation of a compound af-2 by conversion of the substituent isillustrated below:

(In the scheme, each symbol is the same as described above.)

A catalyst of catalytic reduction such as 10% palladium-carbon etc. isadded to a compound ae-2 in a solvent such as tetrahydrofuran, ethylacetate, methanol etc. and it is reacted under the pressure of normal to5 atom, preferably normal to 2 atom of hydrogen atmosphere at 30° C. to120° C., preferably 50° C. to 80° C. for 0.5 to 48 hours, preferably 6to 20 hours to give a compound af-2. Alternatively, the compound af-2 isobtained by a method described in Comprehensive Organic Transformations,Richard C Larock (Mcgraw-Hill).

5) Conversion of a Substituent (3)

A preparation of a compound af-3 by conversion of the substituent isillustrated below:

(In the scheme, R⁹ is hydroxyl, optionally substituted lower alkyl,optionally substituted lower alkoxy, optionally substituted loweralkylthio, optionally substituted lower alkyl amino, optionallysubstituted aromatic carbocyclyloxy, optionally substitutedheterocyclyloxy, optionally substituted aromatic carbocyclylthio,optionally substituted heterocyclylthio, optionally substitutedcarbocyclylamino, optionally substituted heterocyclylamino, cyano,azide, an optionally substituted carbocyclic group, an optionallysubstituted heterocyclic group, optionally substituted carbamoyl etc.and the other symbols are the same as described above.)

A reagent having a substituent corresponding to the objective compoundsuch as ethanol, methanthiol, dimethylamine etc. is added to a compoundae-3 in a solvent such as tetrahydrofuran, ethanol etc. under thepresence of a base such as sodium methoxide, potassium tert-butoxide,sodium hydroxide, sodium hydride etc. or without a base at −10° C. to50° C. and it is reacted for 0.5 to 12 hours, preferably 1 to 8 hours togive a compound af-3. If necessary, a coupling reaction may be carriedout in the same manner as the method for preparing a compound (I-19)described above.

In every step described above, if a starting compound has a functionalgroup which disturb the reaction (e.g., hydroxyl, mercapto, amino,formyl, carbonyl, carboxyl etc.), it is recommended to protect thefunctional group and deprotect it at a subsequent appropriate step witha method described in Protective Groups in Organic Synthesis, Theodora WGreen (John Wiley & Sons) etc.

Further the order of steps may be changed and each reaction intermediatemay be isolated and used in the subsequent step.

Examples of a preferable compound in the present invention include thefollowings:

In a formula (I′)

-   1) a compound in which the ring A′ is phenyl or a    nitrogen-containing aromatic heterocyclic group (hereinafter called    a compound in which the ring A′ is A′1),

a compound in which the ring A′ is benzene, pyridine, indole,benzisoxazole, benzopyrazole, benzofuran, benzothiophene, benzodioxole,or dihydrobenzodioxolane (hereinafter called a compound in which thering A′ is A′2),

a compound in which the ring A′ is benzene (hereinafter called acompound in which the ring A′ is A′3),

a compound in which the ring A′ is pyridine (hereinafter called acompound in which the ring A′ is A′4)

-   2) a compound in which R¹ is optionally substituted lower alkyl    (hereinafter called a compound in which R¹ is R1-1),

a compound in which R¹ is methyl (hereinafter called a compound in whichR¹ is R1-2),

-   3) a compound in which R^(2a) and R^(2b) are each independently    hydrogen, lower alkyl or acyl(hereinafter called a compound in which    R^(2a) and R^(2b) are R2-1),

a compound in which both of R^(2a) and R^(2b) are hydrogens (hereinaftercalled a compound in which R^(2a) and R^(2b) are R2-2),

-   4) a compound in which R^(3a), R^(3b), R^(3c) and R^(3d) are each    independently hydrogen, halogen, hydroxyl, lower alkyl or amino    (hereinafter called a compound in which R^(3a), R^(3b), R^(3c) and    R^(3d) are R3-1),

a compound in which R^(3a), and R^(3b), or R^(3c) and R^(3d) takentogether form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyltogether (hereinafter called a compound in which R^(3a), R^(3b), R^(3c)and R^(3d) are R3-2),

a compound in which R^(3a) and R^(3b), or R^(3c) and R^(3d) are the samesubstituent selected from halogen and lower alkyl (hereinafter called acompound in which R³, R^(3b), R^(3c) and R^(3d) are R3-3),

a compound in which all of R^(3a), R^(3b), R^(3c) and R^(3d) arehydrogens (hereinafter called a compound in which R^(3a), R^(3b), R^(3c)and R^(3d) are R3-4),

-   5) a compound in which n is 0 to 2, R⁴ is each independently    halogen, lower alkoxy, lower alkylamino, lower alkylthio, oxo or    lower alkylenedioxy (hereinafter called a compound in which R⁴ is    R4-1),

a compound in which n is 0 to 2, R⁴ is each independently halogen(hereinafter called a compound in which R⁴ is R4-2),

-   6) a compound in which G is (ii), (iv), (v), (x), (xiii) or (xiv)    above (hereinafter called a compound in which G is G1),

a compound in which G is (ii′), (ii″), (iv′), (v′), (x′), (xiii′) or(xiv′) above (hereinafter called a compound in which G is G2),

a compound in which G is (ii′), (ii″), (iv′), (v′), (x′), (xiii′) or(xiv′) above, and the ring B is optionally substituted pyridyl,optionally substituted pyrazinyl, optionally substituted thiazolyl,optionally substituted isoxazolyl, optionally substitutedbenzothiazolyl, optionally substituted thiazolopyridyl, optionallysubstituted quinolyl, optionally substituted isoquinolyl or optionallysubstituted naphthylidinyl optionally substituted quinazolinyl, oroptionally substituted pyridopyrimidinyl (hereinafter called a compoundin which G is G3),

a compound in which G is (ii′) above (hereinafter called a compound inwhich G is G4),

a compound in which a combination of the ring A′, R¹, R^(2a) and R^(2b),R^(3a), R^(3b), R^(3c) and R^(3d), n and R⁴, and G is as follows;

-   (A′1,R-1,R2-1,R3-1,R4-1,G1),(A′1,R1-1,R2-1,R3-1,R4-1,G2),(A′1,R1-1,R2-1,R3-1,R4-1,    G3),(A′1,R1-1,R2-1,R3-1,R4-1,G4),(A′1,R1-1,R2-1,R3-1,R4-2,G1),(A′1,R1-1,R2-1,R3-1,R    4-2,G2),(A′1,R1-1,R2-1,R3-1,R4-2,G3),(A′1,R1-1,R2-1,R3-1,R4-2,G4),(A′1,R1-1,R2-1,R3-2,R4-1,G1),(A′1,R1-1,R2-1,R3-2,R4-1,G2),(A′1,R1-1,R2-1,R3-2,R4-1,G3),(A′1,R1-1,R2-1,    R3-2,R4-1,G4),(A′1,R1-1,R2-1,R3-2,R4-2,G1),(A′1,R1-1,R2-1,R3-2,R4-2,G2),(A′1,R1-1,R    2-1,R3-2,R4-2,G3),(A′1,R1-1,R2-1,R3-2,R4-2,G4),(A′1,R1-1,R2-1,R3-3,R4-1,G1),(A′1,R1-1,R2-1,R3-3,R4-1,G2),(A′1,R1-1,R2-1,R3-3,R4-1,G3),(A′1,R1-1,R2-1,R3-3,R4-1,G4),(A′1,    R1-1,R2-1,R3-3,R4-2,G1),(A′1,R1-1,R2-1,R3-3,R4-2,G2),(A′1,R1-1,R2-1,R3-3,R4-2,G3),(A′1,R1,R2-1,R3-3,R4-2,G4),(A′1,R1-1,R2-1,R3-4,R4-1,G1),(A′1,R1-1,R2-1,R3-4,R4-1,G    2),(A′1,R1,R2-1,R3-4,R4-1,G3),(A′1,R1-1,R2-1,R3-4,R4-1,G4),(A′1,R1-1,R2-1,R3-4,R4-2,    G1), (A′1,R1-1,R2-1,R3-4,R4-2,    G2),(A′1,R1-1,R2-1,R3-4,R4-2,G3),(A′1,R1-1,R2-1,R3-4,    R4-2,G4),(A′1,R1-1,R2-2,R3-1,R4-1,G1),(A′,R1-1,R2-2,R3-1,R4-1,G2),(A′1,R1-1,R2-2,R    3-1,R4-1,G3),(A′1,R1-1,R2-2,R3-1,R4-1,G4),(A′1,R1-1,R2-2,R3-1,R4-2,G1),(A′1,R1-1,R2-2,R3-1,R4-2,G2),(A′1,R1-1,R2-2,R3-1,R4-2,G3),(A′1,R1-1,R2-2,R3-1,R4-2,G4),(A′1,R1-1,    R2-2,R3-2,R4-1,G1),(A′1,R1-1,R2-2,R3-2,R4-1,G2),(A′1,R1-1,R2-2,R3-2,R4-1,G3),(A′1,R    1-1,R2-2,R3-2,R4-1, G4), (A′11,R1-1,R2-2,    R3-2,R4-2,G1),(A′1,R1-1,R2-2,R3-2,R4-2,G2),    (A′1,R1-1,R2-2,R3-2,R4-2,G3), (A′1,R1-1,    R2-2,R3-2,R4-2,G4),(A′1,R1-1,R2-2,R3-3,R4-1,G1),    (A′1,R1-1,R2-2,R3-3,R4-1,G2),(A′1,R1-1,R2-2,R3-3,R4-1,G3),(A′1,R1-1,R2-2,R3-3,R4-1,    G4),(A′1,R1-1,R2-2,R3-3,R4-2,G1),(A′1,R1-1,R2-2,R3-3,R4-2,G2),(A′1,R1-1,R2-2,R3-3,R    4-2,G3),(A′1,R1-1,R2-2,R3-3,R4-2,G4),(A′1,R1-1,R2-2,R3-4,R4-1,G1),(A′1,R1-1,R2-2,R3-4,R4-1,G2),(A′1,R1-1,R2-2,R3-4,R4-1,G3),(A′1,R1-1,R2-2,R3-4,R4-1,G4),(A′1,R1-1,R2-2,    R3-4,R4-2,G1),(A′1,R1-1,R2-2,R3-4,R4-2,G2),(A′1,R1-1,R2-2,R3-4,R4-2,G3)(A′1,R1-1,R    2-2,R3-4,R4-2,G4),(A′1,R1-2,R2-1,R3-1,R4-1,G1),(A′1,R1-2,R2-1,R3-1,R4-1,G2),(A′1,R1-2,R2-1,R3-1,R4-1,G3),(A′11,R1-2,R2-1,R3-1,R4-1,G4),(A′1,R1-2,R2-1,R3-1,R4-2,G1),(A′1,    R1-2,R2-1,R3-1,R4-2,G2),(A′1,R1-2,R2-1,R3-1,R4-2,G3),(A′1,R1-2,R2-1,R3-1,R4-2,G4),(A′1,R1-2,R2-1,R3-2,R4-1,G1),(A′1,R1-2,R2-1,R3-2,R4-1,G2),(A′1,R1-2,R2-1,R3-2,R4-1,G    3),(A′1,R1-2,R2-1,R3-2,R4-1,G4),(A′1,R1-2,R2-1,R3-2,R4-2,G1),(A′1,R1-2,R2-1,R3-2,R4-2,G2),(A′1,R1-2,R2-1,R3-2,R4-2,G3),(A′1,R1-2,R2-1,R3-2,R4-2,G4),(A′1,R1-2,R2-1,R3-3,    R4-1,G1),(A′1,R1-2,R2-1,R3-3,R4-1,G2),(A′1,R1-2,R2-1,R3-3,R4-1,G3),(A′1,R1-2,R2-1,R    3-3,R4-1,G4),(A′1,R1-2,R2-1,R3-3,R4-2,G1),(A′1,R1-2,R2-1,R3-3,R4-2,G2),(A′1,R1-2,R2-1,R3-3,R4-2,G3),(A′1,R1-2,R2-1,R3-3,R4-2,G4),(A′1,R1-2,R2-1,R3-4,R4-1,G1),(A′1,R1-2,    R2-1,R3-4,R4-1,G2),(A′1,R1-2,R2-1,R3-4,R4-1,G3),(A′1,R1-2,R2-1,R3-4,R4-1,G4),(A′1,R    1-2,R2-1,R3-4,R4-2,G1),(A′1,R1-2,R2-1,R3-4,R4-2,G2),(A′1,R1-2,R2-1,R3-4,R4-2,G3),(A′1,R1-2,R2-1,R3-4,R4-2,G4),(A′1,R1-2,R2-2,R3-1,R4-1,G1),(A′1,R1-2,R2-2,R3-1,R4-1,G2),    (A′1,R1-2,R2-2,R3-1,R4-1,G3),(A′1,R1-2,R2-2,R3-1,R4-1,G4),(A′1,    R1-2,R2-2,R3-1,R4-2,    G1),(A′1,R1-2,R2-2,R3-1,R4-2,G2),(A′1,R1-2,R2-2,R3-1,R4-2,G3),(A′1,R1-2,R2-2,R3-1,R    4-2,G4),(A′1,R1-2,R2-2,R3-2,R4-1,G1),(A′1,R1-2,R2-2,R3-2,R4-1,G2),(A′1,R1-2,R2-2,R3-2,R4-1,G3),(A′1,R1-2,R2-2,R3-2,R4-1,G4),(A′1,R1-2,R2-2,R3-2,R4-2,G1),(A′1,R1-2,R2-2,    R3-2,R4-2,G2),(A′1,R1-2,R2-2,R3-2,R4-2,G3),(A′1,R1-2,R2-2,R3-2,R4-2,G4),(A′1,R1-2,R    2-2,R3-3,R4-1,G1),(A′1,R1-2,R2-2,R3-3,R4-1,G2),(A′1,R1-2,R2-2,R3-3,R4-1,G3),(A′1,R1-2,R2-2,R3-3,R4-1,G4),(A′1,R1-2,R2-2,R3-3,R4-2,G1),(A′1,R1-2,R2-2,R3-3,R4-2,G2),(A′1,    R1-2,R2-2,R3-3,R4-2,G3),(A′1,R1-2,R2-2,R3-3,R4-2,G4),(A′1,R1-2,R2-2,R3-4,R4-1,G1),(A′1,    R1-2,R2-2,R3-4,R4-1,G2), (A′1,R1-2,R2-2,R3-4,R4-1,G3),    (A′1,R1-2,R2-2,R34,R4-1, G 4), (A′1,R1-2,R2-2,R3-4,R4-2,    G1),(A′1,R1-2,R2-2,R3-4,R4-2,G2),    (A′1,R1-2,R2-2,R3-4,R4-2,G3),(A′1,R1-2,R2-2,R3-4,R4-2,G4),-   (A′2, R1-1,R2-1,R3-1,R4-1,G1),(A′2,R1-1,R2-1,R3-1,R4-1,G2),    (A′2,R1-1,R2-1,R3-1,R4-1,    G3),(A′2,R1-1,R2-1,R3-1,R4-1,G4),(A′2,R1-1,R2-1,R3-1,R4-2,GL),(A′2,R1-1,R2-1,R3-1,R    4-2,G2),(A′2,R1-1,R2-1,R3-1,R4-2,G3),(A′2,R1-1,R2-1,R3-1,R4-2,G4),(A′2,R1-1,R2-1,R3-2,R4-1,G1),(A′2,R1-1,R2-1,R3-2,R4-1,G2),(A′2,R1-1,R2-1,R3-2,R4-1,G3),(A′2,R1-1,R2-1,    R3-2,R4-1,G4),(A′2,R1-1,R2-1,R3-2,R4-2,G1),(A′2,R1-1,R2-1,R3-2,R4-2,G2),(A′2,R1-1,R    2-1,R3-2,R4-2,G3),(A′2,R1-1,R2-1,R3-2,R4-2,G4),(A′2,R1-1,R2-1,R3-3,R4-1,G1),(A′2,R1-1,R2-1,R3-3,R4-1,G2),(A′2,R1-1,R2-1,R3-3,R4-1,G3),(A′2,R1-1,R2-1,R3-3,R4-1,G4),(A′2,    R1-1,R2-1,R3-3,R4-2,G1),(A′2,R1-1,R2-1,R3-3,R4-2,G2),(A′2,R1-1,R2-1,R3-3,R4-2,G3),(A′2,R1-1,R2-1,R3-3,R4-2,G4),(A′2,R1-1,R2-1,R3-4,R4-1,G1),(A′2,R1-1,R2-1,R3-4,R4-1,G    2),    (A′2,R1-1,R2-1,R3-4,R4-1,G3),(A′2,R1-1,R2-1,R3-4,R4-1,G4),(A′2,R1-1,R2-1,R3-4,R4-2,G1),(A′2,R1-1,R2-1,R3-4,R4-2,G2),(A′2,R1-1,R2-1,R3-4,R4-2,G3),    (A′2,R1-1, R2-1,R3-4,    R4-2,G4),(A′2,R1-1,R2-2,R3-1,R4-1,G1),(A′2,R1-1,R2-2,R3-1,R4-1,G2),(A′2,R1-1,    R2-2,R    3-1,R4-1,G3),(A′2,R1-1,R2-2,R3-1,R4-1,G4),(A′2,R1-1,R2-2,R3-1,R4-2,G1),(A′2,R1-1,R2-2,R3-1,R4-2,G2),(A′2,R1-1,R2-2,R3-1,R4-2,G3),(A′2,R1-1,R2-2,R3-1,R4-2,G4),(A′2,R1-1,    R2-2,R3-2,R4-1,G1),(A′2,R1-1,R2-2,R3-2,R4-1,G2),(A′2,R1-1,R2-2,R3-2,R4-1,G3),(A′2,R    1-1,R2-2,R3-2,R4-1,G4),(A′2,R1-1,R2-2,R3-2,R4-2,G1),(A′2,R1-1,    R2-2,R3-2,R4-2,A′2,R1-1,R2-2,R3-2,R4-2,G3),(A′2,R1-1,R2-2,R3-2,R4-2,G4),(A′2,R1-1,    R2-2,R3-3,R4-1,G1),    (A′2,R1-1,R2-2,R3-3,R4-1,G2),(A′2,R1-1,R2-2,R3-3,R4-1,G3),(A′2,R1-1,R2-2,R3-3,R4-1,    G4),(A′2,R1-1,R2-2,R3-3,R4-2,G1),(A′2,R1-1,    R2-2,R3-3,R4-2,G2),(A′2,R1-1,R2-2,R3-3,R    4-2,G3),(A′2,R1-1,R2-2,R3-3,R4-2,G4),(A′2,R1-1,R2-2,R3-4,R4-1,G1)(A′2,R1-1,R2-2,R3-4,R4-1,G2),(A′2,R1-1,R2-2,R3-4,R4-1,G3),(A′2,R1-1,R2-2,R3-4,R4-1,G4),(A′2,R1-1,R2-2,    R3-4,R4-2,G1),(A′2,R1-1,R2-2,R3-4,R4-2,G2),(A′2,R1-1,R2-2,R3-4,R4-2,G3),(A′2,R1-1,R    2-2,R3-4,R4-2,G4),(A′2,R1-2,R2-1,R3-1,R4-1,G1),(A′2,R1-2,R2-1,R3-1,R4-1,G2),(A′2,R1-2,R2-1,R3-1,R4-1,G3),(A′2,R1-2,R2-1,R3-1,R4-1,G4),(A′2,R1-2,R2-1,R3-1,R4-2,G1),(A′2,    R1-2,R2-1,R3-1,R4-2,G2),(A′2,R1-2,R2-1,R3-1,R4-2,G3),(A′2,R1-2,R2-1,R3-1,R4-2,G4),(A′2,R1-2,R2-1,R3-2,R4-1,G1),(A′2,R1-2,R2-1,R3-2,R4-1,G2),(A′2,R1-2,R2-1,R3-2,R4-1,G    3),(A′2,R1-2,R2-1,R3-2,R4-1,G4),(A′2,R1-2,R2-1,R3-2,R4-2,G1),(A′2,R1-2,R2-1,R3-2,R4-2,G2),(A′2,R1-2,R2-1,R3-2,R4-2,G3),(A′2,R1-2,R2-1,R3-2,R4-2,G4),(A′2,R1-2,R2-1,R3-3,    R4-1,G1),(A′2,R1-2,R2-1,R3-3,R4-1,G2),(A′2,R1-2,R2-1,R3-3,R4-1,G3),(A′2,R1-2,R2-1,R    3-3,R4-1,G4),(A′2,R1-2,R2-1,R3-3,R4-2,G1),(A′2,R1-2,R2-1,R3-3,R4-2,G2),(A′2,R1-2,R2-1,R3-3,R4-2,G3),(A′2,R1-2,R2-1,R3-3,R4-2,G4),(A′2,R1-2,R2-1,R3-4,R4-1,G1),(A′2,R1-2,    R1-1,R3-4,R4-1,G2),(A′2,R1-2,R2-1,R3-4,R4-1,G3),(A′2,R1-2,R2-1,R3-4,R4-1,G4),(A′2,R    1-2,R2-1,R3-4,R4-2,G1),(A′2,R1-2,R2-1,R3-4,R4-2,G2),(A′2,R1-2,R2-1,R3-4,R4-2,G3),(A′2,R1-2,R2-1,R3-4,R4-2,G4),(A′2,R1-2,R2-2,R3-1,R4-1,G1),(A′2,R1-2,R2-2,R3-1,R4-1,G2),    (A′2,R1-2,R2-2,R3-1,R4-1,G3),(A′2,R1-2,R2-2,R3-1,R4-1,G4),(A′2,R1-2,R2-2,R3-1,R4-2,    G1),(A′2,R1-2,R2-2,R3-1,R4-2,G2);(A′2,R1-2,R2-2,R3-1,R4-2,G3),(A′2,R1-2,R2-2,R3-1,R    4-2,G4),(A′2,R1-2,R2-2,R3-2,R4-1,G1),(A′2,R1-2,R2-2,R3-2,R4-1,G2),(A′2,R1-2,R2-2,R3-2,R4-1,G3),(A′2,R1-2,R2-2,R3-2,R4-1,G4),(A′2,R1-2,R2-2,R3-2,R4-2,G1),(A′2,R1-2,R2-2,    R3-2,R4-2,G2),(A′2,R1-2,R2-2,R3-2,R4-2,G3),(A′2,R1-2,R2-2,R3-2,R4-2,G4),(A′2,R1-2,R    2-2,R3-3,R4-1,G1),(A′2,R1-2,R2-2,R3-3,    R4-1,G2),(A′2,R1-2,R2-2,R3-3,R4-1,G3),(A′2,R1-2,R2-2,R3-3,R4-1,G4),(A′2,R1-2,R2-2,R3-3,R4-2,G1),(A′2,R1-2,R2-2,R3-3,R4-2,G2),(A′2,    R1-2,R2-2,R3-3,R4-2,G3),(A′2,R1-2,R2-2,R3-3,R4-2,G4),(A′2,R1-2,R2-2,R3-4,R4-1,G1),(A′2,R1-2,R2-2,R3-4,R4-1,G2),(A′2,R1-2,R2-2,R3-4,R4-1,G3),(A′2,R1-2,R2-2,R3-4,R4-1,G    4),(A′2,R1-2,R2-2,R3-4,R4-2,G1),(A′2,R1-2,R2-2,R3-4,R4-2,G2),(A′2,R1-2,R2-2,R3-4,R4-2,G3),(A′2,R1-2,R2-2,R3-4,R4-2,G4),-   (A′3,R1-1,R2-1,R3-1,R4-1,G1),(A′3,R1-1,R2-1,R3-1,R4-1,G2),(A′3,R1-1,R2-1,R3-1,R4-1,    G3),(A′3,R1-1,R2-1,R3-1,R4-1,G4),(A′3,R1-1,R2-1,R3-1,R4-2,G1),(A′3,R1-1,R2-1,R3-1,R    4-2,G2),(A′3,R1-1,R2-1,R3-1,R4-2,G3),(A′3,R1-1,R2-1,R3-1,R4-2,G4),(A′3,R1-1,R2-1,R3-2,R4-1,G1),(A′3,R1-1,R2-1,R3-2,R4-1,G2),(A′3,R1-1,R2-1,R3-2,R4-1,G3),(A′3,R1-1,R2-1,    R3-2,R4-1,G4),(A′3,R1-1,R2-1,R3-2,R4-2,G1),(A′3,R1-1,R2-1,R3-2,R4-2,G2),(A′3,R1-1,R    2-1,R3-2,R4-2,G3),(A′3,R1-1,R2-1,R3-2,R4-2,G4),(A′3,R1-1,R2-1,R3-3,R4-1,G1),(A′3,R1-1,R2-1,R3-3,R4-1,G2),(A′3,R1-1,R2-1,R3-3,R4-1,G3),(A′3,R1-1,R2-1,R3-3,R4-1,G4),(A′3,    R1-1,R2-1,R3-3,R4-2,G1),(A′3,R1-1,R2-1,R3-3,R4-2,G2),(A′3,R1-1,R2-1,R3-3,R4-2,G3),(A′3,R1-1,R2-1,R3-3,R4-2,G4),(A′3,R1-1,R2-1,R3-4,R4-1,G1),(A′3,R1-1,R2-1,R3-4,R4-1,G    2),(A′3,R-1-1,R2-1,R3-4,R4-1,G3),(A′3,R1-1,R2-1,R3-4,R4-1,G4),(A′3,R1-1,R2-1,R3-4,R4-2,G1),(A′3,R1-1,R2-1,R3-4,R4-2,G2),(A′3,R1-1,R2-1,R3-4,R4-2,G3),(A′3,R1-1,R2-1,R3-4,    R4-2,G4),(A′3,R1-1,R2-2,R3-1,R4-1,G1),(A′3,R1-1,R2-2,R3-1,R4-1,G2),(A′3,R1-1,R2-2,R    3-1,R4-1,G3),(A′3,R1-1,R2-2,R3-1,R4-1,G4),(A′3,R1-1,R2-2,R3-1,R4-2,G1),(A′3,R1-1,R2-2,R3-1,R4-2,G2),(A′3,R1-1,R2-2,R3-1,R4-2,G3),(A′3,R1-1,R2-2,R3-1,R4-2,G4),(A′3,R-1,    R2-2,R3-2,R4-1,G1),(A′3,R1-1,R2-2,R3-2,R4-1,G2),(A′3,R1-1,R2-2,R3-2,R4-1,G3),(A′3,R    1-1,R2-2,R3-2,R4-1,G4),(A′3,R1-1,R2-2,R3-2,G4-2,G1),(A′3,R1-1,R2-2,R3-2,R4-2,G2),(A′3,R1-1,R2-2,R3-2,R4-2,G3),(A′3,R1-1,R2-2,R3-2,R4-2,G4),(A′3,R1-1,R2-2,R3-3,R4-1,G1),    (A′3,R1-1,R2-2,R3-3,R4-1,G2),(A′3,R1-1,R2-2,R3-3,R4-1,G3),(A′3,R1-1,R2-2,R3-3,R4-1,    G4),(A′3,R1-1,R2-2,R3-3,R4-2,G1),(A′3,R1-1,R2-2,R3-3,R4-2,G2),(A′3,R1-1,R2-2,R3-3,R    4-2,G3),(A′3,R1-1,R2-2,R3-3,R4-2,G4),(A′3,R1-1,R2-2,R3-4,R4-1,G1),(A′3,R1-1,R2-2,R3-4,R4-1,G2),(A′3,R1-1,R2-2,R3-4,R4-1,G3),(A′3,R1-1,R2-2,R3-4,R4-1,G4),(A′3,R1-1,R2-2,    R3-4,R4-2,G1),(A′3,R1-1,R2-2,R3-4,R4-2,G2),(A′3,R1-1,R2-2,R3-4,R4-2,G3),(A′3,R1-1,R2-2-2,R3-4,R4-2,G4),(A′3,R1-2,R2-1,R3-1,R4-1,G1),(A′3,R1-2,R2-1,R3-1,R4-1,G2),(A′3,R1-2,R2-1,R3-1,R4-1,G3),(A′3,R1-2,R2-1,R3-1,R4-1,G4),(A′3,R1-2,R2-1,R3-1,R4-2,G1),(A′3,    R1-2,R2-1,R3-1,R4-2,G2),(A′3,R1-2,R2-1,R3-1,R4-2,G3),(A′3,R1-2,R2-1,R3-1,R4-2,G4),(A′3,R1-2,R2-1,R3-2,R4-1,G1),(A′3,R1-2,R2-1,R3-2,R4-1,G2),(A′3,R1-2,R2-1,R3-2,R4-1,G    3),(A′3,R1-2,R2-1,R3-2,R4-1,G4),(A′3,R1-2,R2-1,R3-2,R4-2,G1),(A′3,R1-2,R2-1,R3-2,R4-2,G2),(A′3,R1-2,R2-1,R3-2,R4-2,G3),(A′3,R1-2,R2-1,R3-2,R4-2,G4),(A′3,R1-2,R2-1,R3-3,    R4-1,G1),(A′3,R1-2,R2-1,R3-3,R4-1,G2),(A′3,R1-2,R2-1,R3-3,R4-1,G3),(A′3,R1-2,R2-1,R    3-3,R4-1,G4),(A′3,R1-2,R2-1,R3-3,R4-2,G1).(A′3,R1-2,R2-1,R3-3,R4-2,G2),(A′3,R1-2,R2-1,R3-3,R4-2,G3),(A′3,R1-2,R2-1,R3-3,R4-2,G4),(A′3,R1-2,R2-1,R3-4,R4-1,G1),(A′3,R1-2,    R2-1,R3-4,R4-1,G2),(A′3,R1-2,R2-1,R3-4,R4-1,G3),(A′3,R1-2,R2-1,R3-4,R4-1,G4),(A′3,R    1-2,R2-1,R3-4,R4-2,G1),(A′3,R1-2,R2-1,R3-4,R4-2,G2),(A′3,R1-2,R2-1,R3-4,R4-2,G3).(A′3,R1-2,R2-1,R3-4,R4-2,G4),(A′3,R1-2,R2-2,R3-1,R4-1,G1),(A′3,R1-2,R2-2,R3-1,R4-1,G2),    (A′3,R1-2,R2-2,R3-1,R4-1,G3),(A′3,R1-2,R2-2,R3-1,R4-1,G4),(A′3,R1-2,R2-2,R3-1,R42,    G1),(A′3,R1-2,R2-2,R3-1,R4-2,G2),(A′3,R1-2,R2-2,R3-1,R4-2,G3),(A′3,R1-2,R2-2,R3-1,R    4-2,G4),(A′3,R1-2,R2-2,R3-2,R4-1,G1),(A′3,R1-2,R2-2,R3-2,R4-1,G2),(A′3,R1-2,R2-2,R3-2,R4-1,G3),(A′3,R1-2,R2-2,R3-2,R4-1,G4),(A′3,R1-2,R2-2,R3-2,R4-2,G1),(A′3,R1-2,R2-2,    R3-2,R4-2,G2),(A′3,R1-2,R2-2,R3-2,R4-2,G3),(A′3,R1-2,R2-2,R3-2,R4-2,G4),(A′3,R1-2,R    2-2,R3-3,R4-1,G1),(A′3,R1-2,R2-2,R3-3,R4-1,G2),(A′3,R1-2,R2-2,R3-3,R4-1,G3),(A′3,R1-2,R2-2,R3-3,R4-1,G4),(A′3,R1-2,R2-2,R3-3,R4-2,G1),(A′3,R1-2,R2-2,R3-3,R4-2,G2),(A′3,    R1-2,R2-2,R3-3,R4-2,G3),(A′3,R1-2,R2-2,R3-3,R4-2,G4),(A′3,R1-2,R2-2,R3-4,R4-1,G1),(A′3,R1-2,R2-2,R3-4,R4-1,G2),(A′3,R1-2,R2-2,R3-4,R4-1,G3),(A′3,R1-2,R2-2,R3-4,R4-1,G    4),(A′3,R1-2,R2-2,R3-4,R4-2,G1),(A′3,R1-2,R2-2,R3-4,R4-2,G2),(A′3,R1-2,R2-2,R3-4,R4-2,G3),(A′3,R1-2,R2-2,R3-4,R4-2,G4),-   (A′4,R1-1,R2-1,R3-1,R4-1,G1),(A′4,R1-1,R2-1,R3-1,R4-1,G2),(A′4,R1-1,R2-1,R3-1,R4-1,    G3),(A′4,R1-1,R2-1,R3-1,R4-1,G4),(A′4,R1-1,R2-1,R3-1,R4-2,G1),(A′4,R1-1,R2-1,R3-1,R    4-2,G2),(A′4,R1-1,R2-1,R3-1,R4-2,G3),(A′4,R1-1,R2-1,R3-1,R4-2,G4),(A′4,R1-1,R2-1,R3-2,R4-1,G1),(A′4,R1-1,R2-1,R3-2,R4-1,G2),(A′4,R1-1,R2-1,R3-2,R4-1,G3),(A′4,R1-1,R2-1,    R3-2,R4-1,G4),(A′4,R1-1,R2-1,R3-2,R4-2,G1),(A′4,R1-1,R2-1,R3-2,R4-2,G2),(A′4,R1-1,R    2-1,R3-2,R4-2,G3),(A′4,R1-1,R2-1,R3-2,R4-2,G4),(A′4,R1-1,R2-1,R3-3,R4-1,G1),(A′4,R1-1,R2-1,R3-3,R4-1,G2),(A′4,R1-1,R2-1,R3-3,R4-1,G3),(A′4,R1-1,R2-1,R3-3,R4-1,G4),(A′4,    R1-1,R2-1,R3-3,R4-2,G1),(A′4,R1-1,R2-1,R3-3,R4-2,G2),(A′4,R1-1,R2-1,R3-3,R4-2,G3),(A′4,R1-1,R2-1,R3-3,R4-2,G4),(A′4,R1-1,R2-1,R3-4,R4-1,G1),(A′4,R1-1,R2-1,R3-4,R4-1,G    2),    (A′4,R1-1,R2-1,R3-4,R4-1,G3),(A′4,R1-1,R2-1,R3-4,R4-1,G4),(A′4,R1-1,R2-1,R3-4,R4-2,G1),(A′4,R1-1,R2-1,R3-4,R4-2,G2),(A′4,R1-1,R2-1,R3-4,R4-2,G3),(A′4,R1-1,R2-1,R3-4,    R4-2,G4), (A′4,R1-1,R2-2,R3-1,R4-1,    G1),(A′4,R1-1,R2-2,R3-1,R4-1,G2),(A′4,R1,R2-2,R    3-1,R4-1,G3),(A′4,R1-1,R2-2,R3-1,R4-1,G4),(A′4,R1-1,R2-2,R3-1,R4-2,G1),(A′4,R1-1,R2-2,R3-1,R4-2,G2),(A′4,R1-1,R2-2,R3-1,R4-2,G3),(A′4,R1-1,R2-2,R3-1,R4-2,G4),(A′4,R1-1,    R2-2,R3-2,R4-1,G1),(A′4,R1-1,R2-2,R3-2,R4-1,G2),(A′4,R1-1,R2-2,R3-2,R4-1,G3),(A′4,R    1-1,R2-2,R3-2,R4-1,G4),(A′4,R1-1,R2-2,R3-2,R4-2,G1),(A′4,R1-1,R2-2,R3-2,R4-2,G2),(A′4,R1-1,R2-2,R3-2,R4-2,G3),(A′4,R1-1,R2-2,R3-2,R4-2,G4),(A′4,R1-1,R2-2,R3-3,R4-1,G1),    (A′4,R1-1,R2-2,R3-3,R4-1,G2),(A′4,R1-1,R2-2,R3-3,R4-1,G3),(A′4,R1-1,R2-2,R3-3,R4-1,    G4),(A′4,R1-1,R2-2,R3-3,R4-2,G1),(A′4,R1-1,R2-2,R3-3,R4-2,G2),(A′4,R1-1,R2-2,R3-3,R    4-2,G3),(A′4,R1-1,R2-2,R3-3,R4-2,G4),(A′4,R1-1,R2-2,R3-4,R4-1,G1),(A′4,R1-1,R2-2,R3-4,R4-1,G2),(A′4,R1-1,R2-2,R3-4,R4-1,G3),(A′4,R1-1,R2-2,R3-4,R4-1,G4),(A′4,R1-1,R2-2,    R3-4,R4-2,G1),(A′4,R1-1,R2-2,R3-4,R4-2,G2),(A′4,R1-1,R2-2,R3-4,R4-2,G3),(A′4,R1-1,R    2-2,R3-4,R4-2,G4),(A′4,R1-2,R2-1,R3-1,R4-1,G1),(A′4,R1-2,R2-1,R3-1,R4-1,G2),(A′4,R1-2,R2-1,R3-1,R4-1,G3),(A′4,R1-2,R2-1,R3-1,R4-1,G4),(A′4,R1-2,R2-1,R3-1,R4-2,G1),(A′4,    R1-2,R2-1,R3-1,R4-2,G2),(A′4,R1-2,R2-1,R3-1,R4-2,G3).(A′4,R1-2,R2-1,R3-1,R4-2,G4),(A′4,R1-2,R2-1,R3-2,R4-1,G1),(A′4,R1-2,R2-1,R3-2,R4-1,G2),(A′4,R1-2,R2-1,R3-2,R4-1,G    3), (A′4,R1-2,R2-1,R3-2,R4-1,G4),(A′4,R1-2,R2-1,R3-2,R4-2,G1),    (A′4,R1-2,R2-1,R3-2,R4-2,G2),(A′4,R1-2,R2-1,R3-2,R4-2,G3),(A′4,R1-2,R2-1,R3-2,R4-2,G4),(A′4,R1-2,R2-1,R3-3,    R4-1,G1),(A′4,R1-2,R2-1,R3-3,R4-1,G2),(A′4,R1-2,R2-1,R3-3,R4-1,G3),(A′4,R1-2,R2-1,R    3-3,R4-1,G4),(A′4,R1-2,R2-1,R3-3,R4-2,G1),(A′4,R1-2,R2-1,R3-3,R4-2,G2),(A′4,R1-2,R2-1,R3-3,R4-2,G3),(A′4,R1-2,R2-1,R3-3,R4-2,G4),(A′4,R1-2,R2-1,R3-4,R4-1,G1),(A′4,R1-2,    R2-1,R3-4,R4-1,G2),(A′4,R1-2,R2-1,R3-4,R4-1,G3),(A′4,R1-2,R2-1,R3-4,R4-1,G4),(A′4,R    1-2,R2-1,R3-4,R4-2,G1),(A′4,R1-2,R2-1,R3-4,R4-2,G2),(A′4,R1-2,R2-1,R3-4,R4-2,G3),(A′    4,R1-2,R2-1,R3-4,R4-2,G4),(A′4,R1-2,R2-2,R3-1,    R4-1,G1),(A′4,R1-2,R2-2,R3-1,R4-1,G2),    (A′4,R1-2,R2-2,R3-1,R4-1,G3),(A′4,R1-2,R2-2,R3-1,R4-1,G4),(A′4,R1-2,R2-2,R3-1,R4-2,    G1),(A′4,R1-2,R2-2,R3-1,R4-2,G2),(A′4,R1-2,R2-2,R3-1,R4-2,G3),(A′4,R-2,R2-2,R3-1,R    4-2,G4),(A′4,R1-2,R2-2,R3-2,R4-1,G1),(A′4,R1-2,R2-2,R3-2,R4-1,G2),(A′4,R1-2,R2-2,R3-2,R4-1,G3),(A′4,R1-2,R2-2,R3-2,R4-1,G4),(A′4,R1-2,R2-2,R3-2,R4-2,G1),(A′4,R1-2,R2-2,    R3-2,R4-2,G2),(A′4,R1-2,R2-2,R3-2,R4-2,G3),(A′4,R1-2,R2-2,R3-2,R4-2,G4),(A′4,R1-2,R    2-2,R3-3,R4-1,G1),(A′4,R1-2,R2-2,R3-3,R4-1,G2),(A′4,R1-2,R2-2,R3-3,R4-1,G3),(A′4,R1-2,R2-2,R3-3,R4-1,G4),(A′4,R1-2,R2-2,R3-3,R4-2,G1),(A′4,R1-2,R2-2,R3-3,R4-2,G2),(A′4,    R1-2,R2-2,R3-3,R4-2,G3),(A′4,R1-2,R2-2,R3-3,R4-2,G4),(A′4,R1-2,R2-2,R3-4,R4-1,G1),(A′4,R1-2,R2-2,R3-4,R4-1,G2),(A′4,R1-2,R2-2,R3-4,R4-1,G3),(A′4,R1-2,R2-2,R3-4,R4-1,G    4),(A′4,R1-2,R2-2,R3-4,R4-2,G1),(A′4,R1-2,R2-2,R3-4,R4-2,G2),(A′4,R1-2,R2-2,R3-4,R4-2,G3)    or (A′4,R1-2,R2-2,R3-4,R4-2,G4).

Compounds of the present invention are useful for treating diseasesinduced by production, secretion or deposition of amyloid β protein, andeffective for the treatment and/or prophylaxis, or improvement ofconditions for Alzheimer's dementia (Alzheimer's disease, seniledementia of Alzheimer type etc.), Down's disease, disturbance of memory,prion disease (Creutzfeldt-Jakob disease etc.), mild cognitiveimpairment (MCI), Dutch-type hereditary cerebral hemorrhage withamyloidosis, cerebral amyloid angiopathy, other degenerated dementia,vascular degenerated mixed dementia, dementia associated withParkinson's disease, dementia associated with progressive supranuclearparalysis, dementia associated with corticobasal degeneration, diffuseLewy Bodies Alzheimer's disease, age-related macular degeneration,Parkinson's disease, or amyloid angiopathy etc.

Since compounds of the present invention have several efficacies such ashaving a potent inhibitory activity against BACE-1 having a highselectivity against other enzymes etc., they can be a drug with lessside effects. Moreover they can be a drug having a wide margin of safetyby choosing an optically active isomer of appropriate stereochemistry.Further they have a lot of merits such as good metabolic stability, highsolubility, high absorbability of oral administration, highbioavailability, good clearance and high transitivity to brain, longhalf-life, high ratio of non protein binding, lower inhibition of hERGchannel and CYP, and/or negative result of Ames Test, and, therefore,they can be superior drugs.

A compound of the present invention may be administrated together withother agent (e.g., other agent for treating Alzheimer's disease such asacetylcholine esterase etc.). The compound can be given in combinationwith an antidementia drug such as donepezil hydrochloride, tacrine,galantamine, rivastigmine, zanapezil, inemantine or vinpocetine, forexample.

A compound of the present invention may be orally administrated aspowder, granule, tablet, capsule, pill or liquid formulation, orparentally administrated as injection, suppository, formulation oftransdermal absorption or inhalation. Also, an effective amount of thecompound may be formulated together with medicinal additives suitablefor the formulation such as an excipient, binder, moistening agent,disintegrant and/or lubricant etc.

Dose of a compounds of the present invention depends on condition ofdiseases, route of administration, age and body weight of a patient, butin the case of oral administration to an adult, the dose range isusually 0.1 μg to 1 g/day, preferably 0.01 to 200 mg/day and in the caseof parenteral administration the dose range is usually 1 g to 10 g/day,preferably 0.1 to 2 g/day.

EXAMPLES

The present invention is illustrated in details by examples and testexamples but the present invention is not limited to these examples.

In EXAMPLES, each abbreviation has the following meaning:

-   Me: methyl-   Et: ethyl-   iPr, Pri isopropyl-   tBu: t-butyl-   Ph: phenyl-   Bn: benzyl-   Boc: tert-butoxycarbonyl-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran-   DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium    chloride n-hydrate-   DMF: N,N-dimethylformamide

Reference Example 1

-   The 1^(st) step: Compound (1) (101.5 g) was cooled to −18° C. and    conc. sulfuric acid (400 ml) was added dropwise in 65 minutes while    the inner temperature was kept at −15° C. or below. Separately    fuming nitric acid (60 ml) was added to conc. sulfuric acid (180 ml)    chilled to 4° C. in 45 minutes while the temperature was kept at    10° C. or below and the resulted mixed acid was added dropwise to    the solution of (1) prepared before in an hour while the temperature    was kept at −30° C. or below. The mixture was stirred at −20° C. or    below for 1.5 hours, poured into 2.5 kg of ice-water and stirred for    an hour. The precipitated crystals were filtered to give    compound (2) (121.5 g).

¹H-NMR (CDCl₃): 2.71 (3H, d, J=5.1 Hz), 7.35 (1H, dd, J=9.3, 9.0 Hz),8.41 (1H, ddd, J=9.0, 3.9, 3.0 Hz), 8.78 (1H, dd, J=6.3, 3.0 Hz).

-   The 2^(nd) step: Compound (2) (20 g) was dissolved in ethanol (400    ml), Pd—C (10% dry)(2.0 g) was added thereto and the mixture was    stirred in a hydrogen atmosphere at room temperature for 2 hours.    Then Pd—C (10% dry)(1.0 g) was added and the mixture was stirred in    a hydrogen atmosphere at room temperature for 1.5 hours, and further    Pd—C (10% dry)(1.0 g) was added and the mixture was stirred in a    hydrogen atmosphere at room temperature for 15 minutes. Pd—C was    filtered off, the solvent was evaporated under reduced pressure and    the residue of compound (3) (15.9 g) was obtained.

¹H-NMR (DMSO-d₆): 2.50 (3H, d, J=4.8 Hz), 5.21 (2H, brs, 1H), 6.78 (1H,ddd, J=8.7, 4.2, 3.0 Hz), 6.94 (1H, dd, J=6.3, 3.0 Hz), 6.99 (1H, dd,J=11.4, 8.7 Hz).

-   The 3rd step: Compound (3) (15.8 g) was dissolved in THF (79 ml),    anhydrous trifluoroacetic acid (16.1 ml) and triethylamine (20.2 ml)    were added under ice cooling and the mixture was stirred for 20    minutes. After the addition of water (30 ml), it was stirred under    ice cooling for 20 minutes and the precipitated crystals were    filtered. The filtrate was extracted with ethyl acetate (80 ml) and    50 ml, the organic layer was washed with water (60 ml), saturated    brine. The crystals filtered previously were dissolved in the    organic layer and dried over sodium sulfate. Sodium sulfate was    filtered, the filtrate was concentrated under reduced pressure and    the residue was dissolved in ethyl acetate under warming. After the    addition of hexane (50 ml) and stirring under ice cooling for 20    minutes, the precipitated crystals were filtered. The mother liquid    was concentrated again under reduced pressure, crystallized by the    addition of ethyl acetate (8 ml) and hexane (12 ml) and compound (4)    (totally 20.4 g) was obtained.

¹H-NMR (CDCl₃): 2.70 (3H, d, J=5.1 Hz), 7.24 (1H, dd, J=10.5, 9.3 Hz),8.00 (1H, dd, J=6.2, 2.9 Hz), 8.21 (1H, m), 8.78 (1H, brs).

-   The 4^(th) step: 1.6 M Vinyl magnesium chloride-THF solution    (122 ml) was dissolved in THF (161 ml), cooled to −40° C. in a    nitrogen atmosphere and a THF (81 ml) solution of compound (4)    (16.1 g) was added dropwise thereto. The reaction solution was    stirred at −40° C. for 20 minutes, 1.6 M vinyl magnesium    chloride-THF solution (20 ml) was further added and the mixture was    stirred at −40° C. for 15 minutes. The reaction solution was poured    into a mixture of chilled ethyl acetate (480 ml), a saturated    aqueous solution of ammonium chloride (80 ml) and water (80 ml) with    stirring, and the organic layer was separated. The aqueous layer was    further extracted with ethyl acetate (200 ml), the organic layers    were combined, washed with water (80 ml), and saturated brine    successively, and dried over sodium sulfate. Sodium sulfate was    filtered, the filtrate was concentrated under reduced pressure and    the residue of compound (5) (22.4 g) was obtained.

¹H-NMR (CDCl₃): 1.74 (3H, d, J=1.2 Hz), 5.16 (1H, dd, J=10.5, 0.9 Hz),5.27 (1H, d, J=17.3, Hz), 6.26 (1H, ddd, J=17.3, 10.5, 1.7 Hz), 7.07(1H, dd, J=11.1, 9.6 Hz), 7.64-7.69 (2H, m), 7.94 (1H, brs).

-   The 5^(th) step: The residue of compound (5) (22.3 g) and thiourea    (5.17 g) were dissolved in acetic acid (112 ml), 1 M HCl-ethyl    acetate (97 ml) was added thereto and the mixture was stirred at    40° C. for 18 hours. The solvent was evaporated under reduced    pressure, toluene (150 ml) was added and again concentrated under    reduced pressure. After repeating the same procedure, crystals were    precipitated. Ethyl acetate (100 ml) was added to the crystalline    residue, the mixture was stirred under ice cooling for an hour and    the crystals were filtered to give compound (6) (15.1 g).

¹H-NMR (DMSO-d₆): 2.08 (3H, s), 4.10 (2H, d, J=7.8 Hz), 5.72 (1H, t,J=7.8 Hz), 7.23-7.32 (1H, m), 7.60-7.69 (2H, m), 9.25 (3H, brs), 11.39(1H, brs).

-   The 6^(th) step: Compound (6) (10.0 g) was dissolved in THF (50 ml),    conc. sulfuric acid (5.74 ml) was added thereto and stirred at    60° C. for 2 hours. After evaporation of TFA under reduced pressure,    ice-water (100 ml) was added. The mixture was stirred under    ice-cooling for an hour, and the precipitated crystals were filtered    to give compound (7) (11.2 g).

¹H-NMR (CDCl₃): 1.72 (3H, s), 2.02-2.18 (1H, m), 2.54-2.76 (2H, m),3.14-3.28 (1H, m), 7.37 (1H, dd, J=11.9, 8.8 Hz), 7.62 (1H, dd, J=7.5,3.0 Hz), 7.80 (1H, ddd, J=8.8, 3.9, 3.0 Hz), 8.77 (1H, brs), 9.38 (1H,brs), 10.66 (1H, brs), 11.50 (1H, brs).

-   The 7^(th) step: MeOH (28 ml), THF (35 ml) and 5 N NaOH (10.9 ml)    were added to compound (7) (7.00 g) and stirred at 50° C. for 4    hours. Toluene (50 ml) was added and extracted, and the aqueous    layer was further extracted with toluene (50 ml) and ethyl acetate    (60 ml). All the organic layers were combined, washed with water and    saturated brine, and dried over sodium sulfate. The solvent was    concentrated under reduced pressure, the resulted crystalline    residue was washed with hexane (20 ml) to give compound (8) (3.45    g).

¹H-NMR (CDCl₃): 1.60 (3H, d, J=1.5 Hz), 1.76-1.87 (1H, m), 2.44-2.54(1H, m), 2.66-2.76 (1H, m), 2.86-2.94 (1H, m), 6.50 (1H, ddd, J=8.7,3.6, 3.0 Hz), 6.66 (1H, dd, J=7.1, 3.0 Hz), 6.81 (1H, dd, J=12.0, 8.7Hz).

Reference Example 2

-   The 1^(st) step: Compound (3)(15.6 g) was dissolved in ethyl acetate    (78 ml), acetic anhydride (10.6 ml) and pyridine (9.07 ml) were    added under ice cooling, and the mixture was stirred for 15 minutes.    Ethyl acetate (100 ml) and water (50 ml) were added, extracted, and    the aqueous layer was extracted with ethyl acetate (50 ml). The    organic layers were combined, washed with 2 M HCl (50 ml), a    saturated solution of sodium bicarbonate (50 ml) and saturated    brine, dried over sodium sulfate. Sodium sulfate was filtered, the    filtrate was concentrated under reduced pressure, and ethyl acetate    (50 ml) and hexane (50 ml) were added to the residue. The mixture    was stirred under ice cooling for 30 minutes and the precipitated    crystals were filtered to give compound (9)(total 14.9 g).

¹H-NMR (CDCl₃): 2.20 (3H, s), 2.66 (3H, d, J=5.1 Hz), 7.13 (1H, dd,J=10.5, 9.0 Hz), 7.70 (1H, dd, J=6.3, 3.0 Hz), 7.79 (1H, bis), 8.11 (1H,ddd, J=9.0, 4.1, 3.0 Hz).

-   The 2^(nd) step: Compound (9)(10.0 g) was dissolved in THF (50 ml),    cooled in ice and sodium hydride (2.25 g) was added in a nitrogen    atmosphere. After stirring for 15 minutes, the resulted mixture was    added dropwise to a solution of 1.6 M vinyl magnesium chloride (86    ml)/THF (70 ml) cooled to −40° C. After stirring at −40° C. for 15    minutes and then 0° C. for 20 minutes, a saturated aqueous solution    of ammonium chloride (50 ml)/water (50 ml) was chilled and added.    The layers were separated and the aqueous layer was extracted with    ethyl acetate (100 ml). Organic layers were combined, washed with    water and saturated brine, dried over sodium sulfate. Sodium sulfate    was filtered, the filtrate was concentrated under reduced pressure    to give a residue of compound (10)(13.7 g).

¹H-NMR (CDCl₃): 1.69 (3H, s), 2.16 (3H, s), 5.12 (1H, d, J=10.5 Hz),5.24 (11H, d, J=17.4 Hz), 6.26 (1H, ddd, J=17.4, 10.5, 1.5 Hz), 6.98(1H, dd, J=11.1, 8.7 Hz), 7.33 (1H, brs), 7.50-7.59 (2H, m).

-   The 3^(rd) step: The residue of compound (10)(6.56 g) and thiourea    (1.88 g) were dissolved in acetic acid (33 ml), 1 M HCl-acetic acid    (37 ml) was added and stirred at 40° C. for 7 hours. The solvent was    evaporated under reduced pressure, toluene (50 ml) was added and    concentrated again under reduced pressure. The same procedure was    repeated again, ethyl acetate (30 ml) was added to the residue and    stirred at room temperature overnight. The precipitate was filtered    to give compound (11)(5.77 g).

¹H-NMR (DMSO-d₆): 2.03 (3H, s), 2.06 (3H, s), 4.09 (2H, d, J=7.5 Hz),5.67 (1H, t, J=7.5 Hz), 7.12 (1H, dd, J=10.7, 8.9 Hz), 7.46-7.59 (2H,m), 9.24 (4H, brs), 10.11 (1H, s).

-   The 4^(th) step: compound (11)(5.16 g) was dissolved in conc.    sulfuric acid (15.5 ml) and stirred at room temperature for an hour.    It was poured into ice-water (100 ml), adjusted to pH 10 by the    addition of an aqueous solution of potassium hydroxide and extracted    with ethyl acetate (200 ml) and a little amount of MeOH. The organic    layer was washed with water and saturated brine, dried over sodium    sulfate. Sodium sulfate was filtered, the filtrate was concentrated    under reduced pressure, ethyl acetate (20 ml) and hexane (15 ml)    were added to the residue and the precipitate was filtered. The    filtrate was concentrated, ethyl acetate (5 ml) and hexane (5 ml)    were added and the precipitate was filtered to give compound    (12)(total 3.16 g).

¹H-NMR (CDCl₃): 1.62 (3H, d, J=0.9 Hz), 1.80-1.91 (1H, m), 2.16 (3H, s),2.47-2.58 (1H, m), 2.62-2.73 (1H, m), 2.87-2.98 (1-1H, m), 4.36 (2H,brs), 6.99 (11H, dd, J=11.7, 8.7 Hz), 7.14 (1H, dd, J=7.1, 3.0 Hz), 7.80(1H, ddd, J=8.7, 4.2, 3.0 Hz), 7.97 (1H, brs),

-   The 5^(th) step: Compound (12)(2.50 g) was suspended in ethanol (25    ml), 6 M HCl (10.2 ml) was added and the mixture was stirred at    90° C. for 3 hours. 2 M NaOH (35 ml) was added, the organic solvent    was evaporated and the residue was extracted with ethyl acetate (70    ml). The aqueous layer was further extracted with ethyl acetate (30    ml), organic layers were combined, washed with water and saturated    brine, and dried over sodium sulfate. Sodium sulfate was filtered,    the filtrate was concentrated under reduced pressure, and the    crystalline residue was washed with ethyl acetate (3 ml) and hexane    (10 ml). The crystals were filtered to give compound (8) total 1.22    g).

Reference Example 3

-   The 1^(st) step: A ethanol solution of 20% sodium ethoxide (5.12 ml,    16.2 mmol, 40 eq.) was added to compound (13)(150 mg, 406 μmol) and    stirred at room temperature for 6 hours. The reaction solvent was    evaporated under reduced pressure, 2 M hydrochloric acid (8.12 ml,    16.2 mmol, 40 eq.) was added to the resulted residue and extracted    with chloroform. The extracting solution was washed with water and    dried over anhydrous sodium sulfate. The crude product (189 mg) was    obtained by evaporation of the solvent under reduced pressure, to    which 4 M HCl-ethyl acetate solution (1.89 ml) was added and the    mixture was stirred at room temperature for 14 hours. A saturated    aqueous solution of sodium bicarbonate was added to the reaction    solution, extracted with ethyl acetate and dried over anhydrous    sodium sulfate. The solvent was evaporated under reduced pressure to    give compound (14)(90.8 mg, 76% yield) as a yellow powder.

¹H NMR (CDCl₃) δ1.52 (3H, t. J=6.8 Hz), 1.67 (3H, s), 1.93-2.00 (1H, m),2.60-2.67 (2H, m), 2.94-3.00 (1H, m), 4.19 (2H, q, J=6.8 Hz), 6.93 (1H,d, J=9.3 Hz), 8.14 (1H, dd, J=8.7, 2.4 Hz), 8.31 (1H, d, J=2.5 Hz).

-   The 2^(nd) step: A powder of 10% palladium-carbon (45.4 mg) was    added to a methanol (908 μl) solution of compound (14)(90.8 mg, 307    mmol) and the mixture was stirred in a hydrogen atmosphere for 22    hours. The reaction mixture was filtered through a Celite pad and    the filtrate was evaporated under reduced pressure. The residue was    washed with ethyl acetate to give compound (15)(65.8 mg, 81% yield)    as an yellow powder.

¹H NMR (DMSO-d₆) δ 1:29 (3H, t, J=6.9 Hz), 1.45 (3H, s), 1.51-1.58 (1H,m), 2.46-2.48 (1H, m), 2.61-2.64 (1H, m), 2.80-2.83 (1H, m), 3.85-3.91(2H, m), 6.38 (1H, dd, J=8.3, 2.5 Hz), 6.52 (1H, d, J=2.4 Hz), 6.67 (1H,d, J=8.6 Hz)

Reference Example 4

-   The 1^(st) step: 3′-Bromoacetophenone (15.0 g) and compound    (16)(9.13 g) were dissolved in tetrahydrofuran (250 ml), and    tetraethoxytitanium (39.5 ml) was added thereto at room temperature    with stirring. Then the reaction mixture was stirred at 75° C. for 5    hours, and saturated brine was added after disappearance of    compound (I) was confirmed. Titanium oxide formed in the reaction    was filtered off, the filtrate was extracted with ethyl acetate, the    organic layer was dried over anhydrous magnesium sulfate and the    solvent was evaporated under reduced pressure. The residue was    purified with a column chromatography to give compound (17)(20.1 g).

¹H-NMR (CDCl₃): 1.33 (9H, s), 2.75 (3H, s), 7.30 (1H, t. J=7.8)7.59-7.63 (1H, m), 7.79 (1H, d, J=7.8) 8.0 (1H, s)

-   The 2^(nd) step: A 2.64 M hexane solution of n-butyllithium    (79.5 ml) is added dropwise to a tetrahydrofuran (100 ml) solution    of diisopropylamine (42.1 ml) in a nitrogen atmosphere at −78° C.    After stirring at 0° C. for 30 minutes, the reaction solution was    again cooled to −78° C. and tert-butyl acetate (26.9 ml) dissolved    in tetrahydrofuran (100 ml) is added dropwise. After stirring at    −78° C. for 30 minutes, chlorotriisopropoxytitaniunm dissolved in    tetrahydrofuran (150 ml) is added dropwise. After stirring at the    same temperature for 70 minutes, compound (2)(20.1 g) dissolved in    tetrahydrofuran (100 ml) was added dropwise. After then, the    reaction solution was stirred at −78° C. for 3 hours, and an aqueous    solution of ammonium chloride was added after disappearance of    compound (2) was confirmed. Titanium oxide formed in the reaction    was filtered off, the filtrate was extracted with ethyl acetate, the    organic layer was washed with saturated brine and dried over    anhydrous magnesium sulfate. The solvent was evaporated under    reduced pressure to give a crude product of compound (18)(26.4 g).-   The 3^(rd) step: The crude product of compound (18)(26.4 g) was    dissolved in toluene (80 ml), the solution was added dropwise to a 1    M solution of aluminum diisobutyl hydride in toluene (253 ml) with    stirring at 0° C. The reaction solution was stirred at room    temperature for 1.5 hours and 1 N hydrochloric acid solution was    added after disappearance of compound (3) was confirmed. The mixture    was extracted with ethyl acetate, the organic layer was washed with    saturated brine and dried over anhydrous magnesium sulfate. The    solvent was evaporated under reduced pressure and the residue was    purified by crystallization to give compound (19)(18.1 g).

¹H-NMR (CDCl₃): 1.28 (9H, s), 1.71 (3H, s), 2.19-2.24 (2H, m), 3.27-3.32(11H, n), 3.54-3.66 (1H, m), 3.87-3.97 (1H, m), 5.10-5.11 (1H, m), 7.22(1H, t. J=8.1) 7.32-7.41 (2H, m), 7.56-7.58 (1H, m)

-   The 4^(th) step: Compound (19)(18. g) was dissolved in methanol (30    ml), and 10% hydrochloric acid in methanol (130 ml) was added    dropwise therein at room temperature. The reaction solution was    stirred at room temperature for 4 hours and 1 N hydrochloric acid    was added after disappearance of compound (4) was confirmed. The    mixture was extracted with ethyl acetate, the aqueous layer was    neutralized with a 2 N aqueous solution of sodium hydroxide and    extracted with ethyl acetate. The organic layer was dried over    anhydrous magnesium sulfate and the solvent was evaporated under    reduced pressure to give a crude product of compound (20)(14.1 g).-   The 5^(th) step: The crude product of compound (20)(32.8 g) and    potassium carbonate (37.1 g) were dissolved in a mixed solvent of    toluene (450 ml) and water (225 ml) and thiophosgene (15.3 ml) was    added dropwise cooled at 0° C. with stirring. After then, the    reaction solution was stirred at 0° C. for an hour and water was    added when disappearance of compound (5) was confirmed. The mixture    was extracted with ethyl acetate and the organic layer was washed    with brine and dried over anhydrous magnesium sulfate. The solvent    was evaporated under reduced pressure to give a crude product of    compound (21)(38.4 g).-   The 6^(th) step: The crude product of (21)(38.4 g) was dissolved in    toluene (384 ml), and thionyl chloride (29.4 ml) and    N,N-dimethylformamide (1.04 ml) were added dropwise at 0° C. with    stirring. After then, the reaction solution was stirred at 80° C.    for 5 hours, and after disappearance of compound (6) was confirmed,    the reaction solution was evaporated under reduced pressure to give    a crude product of compound (22)(40.9 g).-   The 7^(th) step: The crude product of compound (22)(40.9 g) was    dissolved in tetrahydrofuran (250 ml) and 25% ammonia-water (250 ml)    was added with stirring at 0° C. After then the reaction solution    was stirred at room temperature for 16 hours, and a saturated    aqueous solution of sodium bicarbonate was added after disappearance    of compound (21) was confirmed. The organic layer was separated and    the aqueous solution was extracted with dichloromethane. The organic    layers were combined, dried over anhydrous magnesium sulfate and    evaporated under reduced pressure to give a crude product of    compound (23)(38.3 g).-   The 8^(th) step: The crude product of compound (23)(38.3 g) is    dissolved in tetrahydrofuran (383 ml), di-tert-butyl dicarbonate    (61.5 g) and N,N-dimethylaminopyridine (1.64 g) are added and the    mixture was stirred at room temperature for 72 hours. After    disappearance of compound (23) was confirmed, the solvent was    evaporated under reduced pressure. The residue was purified with a    silicagel column chromatography to give compound (24)(45.3 g)

¹H-NMR (CDCl₃): 1.54 (9H, s), 1.57 (3H, s), 1.96 (2H, t, J=6.0),2.80-2.92 (1H, m), 3.00-3.13 (1H, m), 7.21 (1H, t. J=8.1) 7.28-7.41 (2H,m), 7.52-7.55 (1H, m)

-   The 9^(th) step: In a nitrogen atmosphere, compound (24)(12.1 g),    trisdibenzylideneacetonedipalladilum (1.14 g) and    dicyclohexylbiphenylphosphine (0.88 g) were dissolved in toluene    (125 ml), and a 1.6 M solution of lithium hexamethyldisilazide in    tetrahydrofuran (46.9 ml) was added with stirring at room    temperature. The reaction solution was warmed up to 80° C. and    stirred for 16 hours. After disappearance of compound (21) was    confined, the reaction solution was cooled at 0° C. and diethyl    ether and 1 N hydrochloric acid were added. After stirring at 0° C.    for 10 minutes, the solution was neutralized with a saturated    aqueous solution of sodium carbonate. It was extracted with ethyl    acetate, the organic layer was washed with saturated brine and dried    over anhydrous magnesium sulfate. The solvent was evaporated under    reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (25)(6.84 g).

¹H-NMR (CDCl₃): 1.51 (9H, s), 1.69 (3H, s), 2.01-2.12 (1H, m), 2.40-2.51(1H, m), 2.67-2.76 (2H, m), 6.55-6.67 (3H, m), 7.15 (1H, t. J=8.1).

Reference Example 5

-   The 1^(st) step: After the addition of compound (I)(70.00 g) to    conc. sulfuric acid (279 ml) cooled in an acetonitrile/dry ice bath    with stirring, a mixture of fuming nitric acid (42 ml) and conc.    sulfuric acid (98 ml) were added dropwise. After stirring for 16    minutes, the mixture was gradually poured into ice, the precipitated    crystals were filtered and dried to give compound (2)(77.79 g).

¹H-NMR (CDCl₃) δ: 2.71 (3H, d, J=4.9 Hz), 7.34 (1H, t, J=9.3 Hz), 8.40(1H, ddd, J=9.3, 6.2, 3.0 Hz), 8.78 (1H, dd, J=6.2, 3.0 Hz).

-   The 2^(nd) step: A solution of compound (2)(73.94 g),    (R)-(+)-2-methyl-2-propanesulfinamide (53.82 g) and tetraethyl    orthotitanate (230.20 g) in tetrahydrofuran (500 ml) were reacted    for 2.5 hours under heating to reflux, and then the reaction mixture    was gradually poured into ice and the resulted insoluble materials    were filtered. It was extracted with ethyl acetate, the organic    layer was dried over anhydrous magnesium sulfate and evaporated    under reduced pressure. The residue was crystallized from ethyl    acetate/n-hexane to give compound (26)(85.44 g).

¹H-NMR (CDCl₃) δ: 1.34 (9H, s), 2.81 (3H, d, J=3.5 Hz), 7.29 (1H, t,J=8.9 Hz), 8.31 (1H, dt, J=8.9, 2.9 Hz), 8.55 (1H, dd, J=6.3, 2.9 Hz).

-   The 3^(rd) step: A solution of tert-butyl acetate (6.08 g) in    tetrahydrofuran (10 ml) was added dropwise to a 2 M solution of    lithium diisopropylamide/tetrahydrofuran/n-heptane/ethylbenzene    (27.9 ml) cooled in an acetone/dry ice bath with stirring. After    stirring for 20 minutes, a solution of chlorotitanium isopropoxide    (17.5 ml) in tetrahydrofuran (30 ml) was added dropwise, the mixture    was stirred for an hour and a solution of compound (26)(5.00 g) in    tetrahydrofuran (10 ml) was added dropwise. After reacting for an    hour, the reaction solution was gradually poured into an aqueous    solution of ammonium chloride cooled in ice with stirring and the    resulted insoluble materials were filtered. It was extracted with    ethyl acetate, the organic layer was dried over anhydrous sodium    sulfate. The solvent was evaporated under reduced pressure and the    residue was purified with a silicagel column chromatography to give    compound (27)(5.49 g).

¹H-NMR (CDCl₃): 1.30 (9H, s), 1.35 (9H, s), 1.86 (3H, s), 3.11 (1H, dd,J=16.2, 2.1 Hz), 3.26 (1H, dd, J=16.2, 2.1 Hz), 5.55 (1H, s), 7.18 (1H,dd, J=11.1, 8.9 Hz), 8.18 (1H, ddd, J=8.9, 4.0, 2.9 Hz), 8.53 (1H, dd,J=7.0, 2.9 Hz).

Ratio of diastereomers (3S:3R=97:3) HPLC Column: CHIRALPAK AS-RH,Detection:254 nm: Column temp.: 25° C., Mobile phase: 40% MeCNaq., Flowrate: 0.5 ml/min.

Note: As to the stereochemistry of compound (27) obtained above, it isknown that 3S-isomer is preferentially prepared as written in theliterature A etc. and it is also possible to prepare each diastereomerselectively by choosing appropriate metal species and/or a reactioncondition.

Literature A: (1) T. Fujisawa et al., Tetrahedron Lett., 37, 3881-3884(1996), (2) D. H. Hua et al, Sulfur Reports, vol. 21, pp. 211-239(1999), (3) Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), (4)Yong Qin et al., J. Org. Chem., 71, 1588-1591 (2006).

-   The 4^(th) step: A solution of 4 M HCl/1,4-dioxane (50 ml) was added    to compound (27)(12.74 g) and the mixture was stirred at 80° C. for    an hour, diethyl ether (50 ml) was added, the precipitated crystals    were filtered and dried to give compound (28)(7.67 g).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, s), 3.25 (2H, s), 7.62 (1H, dd, J=11.4,9.4 Hz), 8.33-8.48 (2H, m).

-   The 5^(th) step: A solution of 1 M tetrahydrofuran-borane in    tetrahydrofuran (2029 ml) was added dropwise to a solution of    compound (28)(141.32 g) in tetrahydrofuran (707 ml) cooled in ice    with stirring and it was reacted for 3 hours and 6 minutes. The    reaction mixture was poured into a mixture of sodium bicarbonate    (511 g), ice (1500 g) and ethyl acetate (3000 ml) stirred at room    temperature, extracted with ethyl acetate and the organic layer was    dried over anhydrous sodium sulfate. The solvent was evaporated    under reduced pressure to give compound (29)(115.46 g) as a crude    product.-   The 6^(th) step: Toluene (25 ml) and water (12.5 ml) were added to    the compound (29) (3.76 g) obtained in the 5th step and stirred    under ice cooling. After the addition of potassium carbonate (7.97    g), thiophosgene (2.85 g) was added dropwise. After reacting for 3    hours, water was added, extracted with toluene and the organic layer    was dried over anhydrous magnesium sulfate. A part of the solvent    was evaporated under reduced pressure to give compound (30) as a    crude product.-   The 7^(th) step: Compound (30) obtained in the 6th step was    dissolved in toluene (17.4 ml) and thionyl chloride (6.67 g) and    N,N-dimethylformamide (0.128 ml) were added with stirring at room    temperature. The mixture was stirred at 80° C. for 2 hours, water    was added, extracted with toluene and concentrated under reduced    pressure to give compound (31)(4.03 g) as a crude product.-   The 8^(th) step: Compound (31)(4.03 g) obtained in the 7th step was    dissolved in tetrahydrofuran (23.8 ml) and 28% ammonia-water    (23.8 ml) was added under ice cooling with stirring. The mixture was    stirred at room temperature for 3 days, the reaction solution was    concentrated under reduced pressure and ethyl acetate was added    therein. Conc. hydrochloric acid (6 ml) was added under ice cooling    with stirring, the precipitated crystals were washed with ethyl    acetate and water and dried to give compound (32)(2.14 g).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, s), 2.13-2.24 (1H, m), 2.68-2.74 (2H, m),3.19-3.25 (1H, m), 7.63 (1H, dd, J=11.4, 8.9 Hz), 8.07 (1H, dd, J=7.0,3.5 Hz), 8.36 (1H, dt, J=8.9, 3.5 Hz), 11.22 (1H, s).

-   The 9^(th) step: Compound (32) (100 mg) was dissolved in methanol (2    ml), 10% palladium-carbon powder (50 mg) was added, and the mixture    was stirred in a hydrogen atmosphere at room temperature for 18    hours. Insoluble materials were filtered off, the filtrate was    evaporated under reduced pressure, sodium carbonate and water were    added therein and extracted with ethyl acetate. The organic layer    was dried over anhydrous sodium sulfate and the solvent was    evaporated under reduced pressure to give compound (33)(68 mg).

¹H-NMR (CDCl₃): 1.59 (3H, s), 1.81 (1H, ddd, J=14.1, 10.9, 3.5 Hz), 2.47(1H, ddd, J=14.1, 5.9, 3.5 Hz), 2.71 (1H, td, J=10.9, 3.5 Hz), 2.89 (1H,ddd, J=10.9, 5.9, 3.5 Hz), 3.57 (2H, br s), 6.49 (1H, dt, J=8.5, 3.3Hz), 6.67 (1H, dd, J=6.9, 3.3 Hz), 6.80 (1H, dd, J=11.8, 8.5 Hz).

Reference Example 6

-   The 1^(st) step: A solution of compound (38)(5.00 g),    (R)-(+)-2-methyl-2-propanesulfinamide (3.33 g) and tetraethyl    orthotitanate (17.11 g) in tetrahydrofuran (50 ml) was reacted under    heating to reflux for 7 hours, and then, it was poured portionwise    into saturated brine and the resulted insoluble materials were    filtered off. It was extracted with ethyl acetate, the organic layer    was dried over anhydrous magnesium sulfate and concentrated under    reduced pressure. The residue was purified with a silicagel column    chromatography to give compound (39)(6.37 g).

¹H-NMR (CDCl₃) δ: 1.34 (9H, s), 2.79 (3H, s), 8.26 (1H, t, J=2.3 Hz),8.76 (1H, d, J=2.3 Hz), 8.96 (1H, d, J=2.3 Hz).

-   The 2^(nd) Step: A solution of 2.66 M n-butyllithium/n-hexane    (32.4 ml) was added dropwise to a solution of diisopropylamine    (9.36 g) in tetrahydrofuran (39 ml) cooled in an acetone/dry ice    bath with stirring and the mixture was stirred under ice cooling for    30 minutes. The reaction solution was stirred again in an    acetone/dry ice bath and a solution of tert-butyl acetate (4.88 g)    in tetrahydrofuran (8 ml) was added dropwise. After stirring for    minutes, a solution of chlorotitanium triisopropoxide (23.00 g) in    tetrahydrofuran (88 ml) was added dropwise. After stirring for 10    minutes, a solution of compound (39)(6.37 g) in tetrahydrofuran    (65 ml) was added dropwise. After reacting for 30 minutes, the    reaction solution was poured portionwise into an aqueous solution of    ammonium chloride and the resulted insoluble materials were filtered    off. It was extracted with ethyl acetate and the organic layer was    dried over anhydrous sodium sulfate. The solvent was evaporated    under reduced pressure to give compound (40)(8.03 g) as a crude    product.-   The 3^(rd) step: Lithium aluminium hydride (2.85 g) was added    portionwise to a solution of the compound (40×8.03 g) obtained in    the 2nd step in tetrahydrofuran (100 ml) cooled in ice with stirring    and the mixture was stirred for 2 hours. Acetone, water, and a 1N    aqueous solution of sodium hydroxide were added portionwise and the    mixture was stirred at room temperature for 30 minutes. The    insoluble materials were filtered off and extracted with ethyl    acetate. The organic layer was dried over anhydrous magnesium    sulfate and concentrated under reduced pressure to give compound    (41)(5.83 g) as a crude product.-   The 4^(th) step: A solution of 10% HCl/methanol (60 ml) was added to    a solution of the compound (41)(5.83 g) obtained in the 3rd step in    methanol (60 ml) cooled in ice with stirring and stirred at room    temperature for 16 hours. The reaction solution was made alkaline by    the addition of water and potassium carbonate, extracted with    chloroform, the organic layer was dried over anhydrous sodium    sulfate and concentrated under reduced pressure to give compound    (42)(5.07 g) as a crude product.-   The 5th step: Imidazole (2.24 g) and t-butyldimethylsilyl chloride    (3.77 g) were added to a solution of the compound (42)(5.07 g)    obtained in the 4th step in N,N-dimethylformamide (26 ml) with    stirring at room temperature and the mixture was stirred for 1 hour    and 40 minutes. After extraction with ethyl acetate, the organic    layer was washed with saturated brine and dried over anhydrous    sodium sulfate. The solvent was evaporated under reduced pressure    and the residue was purified with a silicagel column chromatography    to give compound (43)(3.82 g).

¹H-NMR (CDCl₃) δ: −0.04 (3H, s), −0.01 (3H, s), 0.85 (9H, s), 1.51 (3H,s), 1.98 (2H, t, J=6.0 Hz), 3.49-3.54 (1H, m), 3.65 (1H, dt, J=11.1, 6.0Hz), 8.02 (1H, t, J=2.2 Hz), 8.53 (1H, d, J=2.2 Hz), 8.63 (1H, d, J=2.2Hz).

-   The 6^(th) step: Toluene (25 ml) and water (13 ml) were added to    compound (43)(3.82 g) and stirred under ice cooling. After the    addition of potassium carbonate (5.14 g), thiophosgene (1.83 g) was    added dropwise. After reacting for 2 hours, water was added,    extracted with chloroform and the organic layer was dried over    anhydrous magnesium sulfate. A part of the solvent was evaporated    under reduced pressure to give compound (44) as a crude product.-   The 7^(th) step: Thionyl chloride (4.43 g) and N,N-dimethylformamide    (0.08 ml) were added to a solution of the compound (7) obtained in    the 6^(th) step in toluene (25 ml) with stirring at room    temperature. The mixture was stirred at 80° C. for 5 hours,    concentrated under reduced pressure to give compound (45)(5.03 g) as    a crude product.-   The 8^(th) step: 28% Ammonia water (60 ml) was added to a solution    of the compound (45)(5.03 g) obtained in the 7th step in    tetrahydrofuran (60 ml) stirred under ice cooling and the mixture    was stirred at room temperature for 14 hours. The reaction solution    was concentrated under reduced pressure to give compound    (46)(4.92 g) as a crude product.-   The 9^(th) step: A mixture of the compound (46)(4.92 g) obtained in    the 8th step, di-t-butyl dicarbonate (9.28 g), triethylamine (3.23    g), 4-dimethylaminopyridine (0.13 g) and tetrahydrofuran (106 ml)    was stirred at room temperature for 3 days. The insoluble materials    were filtered off, water was added to the filtrate and extracted    with ethyl acetate. The organic layer was dried over anhydrous    sodium sulfate and concentrated under reduced pressure to give    compound (47)(8.31 g) as a crude product.-   The 10^(th) step: A mixture of the compound (47)(8.31 g) obtained in    the 9th step, di-t-butyl dicarbonate (6.96 g), triethylamine (3.23    g), 4-dimethylaminopyridine (0.13 g) and tetrahydrofuran (50 ml),    was stirred at room temperature for an hour. After the addition of    water, it was extracted with ethyl acetate and the organic layer was    dried over anhydrous magnesium sulfate. The solvent was evaporated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (48)(1.23 g).

¹H-NMR (CDCl₃): 1.53 (18H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8, 9.4,3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.9, 1.9 Hz), 2.91 (1H, ddd, J=12.9,3.9, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.4, 3.9 Hz), 7.89 (1H, t, J=2.1Hz), 8.55-8.57 (2H, m).

-   The 11th step: Compound (48)(190 mg),    trisdibenzylideneacetonedipalladitun (54 mg),    dicyclohexylbiphenylphosphine (41 mg) were dissolved in toluene (5    ml), stirred at room temperature, and 1.6 M solution of lithium    hexamethyldisilazide in tetrahydrofuran (0.73 ml) was added therein.    The reaction solution was warmed up to 85° C. and stirred for 9    hours, then, it was cooled in ice and diethyl ether and a 1 N    solution of hydrochloric acid were added. After stirring for 10    minutes, it was neutralized by the addition of a saturated aqueous    solution of sodium carbonate and extracted with dichloromethane. The    organic layer was dried over anhydrous sodium sulfate, concentrated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (49)(27 mg).

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 1.68 (3H, s), 2.12 (1H, ddd, J=14.8,11.0, 3.0 Hz), 2.38-2.47 (1H, m), 2.64-2.70 (1H, m), 2.78-2.82 (1H, m),3.80 (2H, br s), 6.90 (1H, t, J=2.4 Hz), 7.98 (1H, dd, J=10.4, 2.4 Hz).

Reference Example 7

-   The 1^(st) step: A solution of compound (50)(38.93 g),    (R)-(+)-2-methyl-2-propanesulfinamide (13.20 g) and tetraethyl    orthotitanate (67.76 g) in tetrahydrofuran (389 ml) was reacted    under heating to reflux for 4 hours. A saturated aqueous solution of    ammonium chloride was added portionwise therein and the resulted    insoluble materials were filtered off. The filtrate was concentrated    and dried over anhydrous magnesium sulfate. The solvent was    evaporated under reduced pressure to give compound (51)(30.52 g) as    a crude product.

¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 2.83 (3H, s), 7.55-7.65 (2H, m), 8.06(1H, d, J=8.5 Hz).

-   The 2^(nd) step: A solution of tert-butyl acetate (22.99 g) in    tetrahydrofuran (148 ml) was added dropwise to a 2.0 M solution of    lithium diisoproprylamide/n-heptane/ethylbenzene/tetrahydrofuran    (202.5 ml) cooled in an acetone/dry ice bath with stirring. After    stirring for 45 minutes, a solution of chlorotitanium    triisopropoxide (108.36 g) in tetrahydrofuran (342 ml) was added    dropwise and stirred for 40 minutes. A solution of the compound    (51)(30.52 g) in tetrahydrofuran (342 ml) was added dropwise and    reacted for an hour. The reaction solution was poured portionwise    into an aqueous solution of ammonium chloride with stirring under    ice cooling and the resulted insoluble materials were filtered off.    It was extracted with ethyl acetate and the organic layer was dried    over anhydrous magnesium sulfate. The solvent was evaporated under    reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (52)(27.40 g).

¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 1.35 (9H, s), 1.65 (3H, s), 3.01 (1H, d,J=16.5 Hz), 3.38 (1H, d, J=16.5 Hz), 5.60 (1H, s), 7.31 (1H, dd, J=5.9,2.7 Hz), 7.48-7.50 (2H, m).

-   The 3^(rd) step: Lithium aluminium hydride (5.67 g) was added    portionwise to a solution of the compound (52)(22.40 g) in    tetrahydrofuran (336 ml) stirred in an ice salt bath and stirred for    7 hours. After the addition of acetone, water and a 1 N aqueous    solution of sodium hydroxide, the insoluble materials were filtered    off and extracted with ethyl acetate. The organic layer was dried    over anhydrous sodium sulfate and concentrated under reduced    pressure to give compound (53)(18.75 g) as a crude product.-   The 4^(th) step: A solution of 10% HCl/methanol (94 ml) was added to    a solution of the compound (53)(18.75 g) obtained in the 3rd step in    methanol (94 ml) stirred under ice cooling and stirred at room    temperature for 1.5 hours. The reaction solution was made alkaline    by the addition of water and potassium carbonate and extracted with    chloroform. The organic layer was dried over anhydrous sodium    sulfate and concentrated under reduced pressure to give compound    (54)(21.03 g) as a crude product.-   The 5^(th) step: Imidazole (5.49 g) and tert-butyldimethylsilyl    chloride (10.53 g) were added to a solution of the compound    (54)(21.03 g) in N,N-dimethylformamide (210 ml) stirred at room    temperature and the mixture was stirred for an hour. After    extraction with ethyl acetate, the organic layer was washed with    saturated brine and dried over anhydrous sodium sulfate. The solvent    was evaporated under reduced pressure and the residue was purified    with a silicagel column chromatography to give compound (55)(20.12    g).

¹H-NMR (CDCl₃) δ: −0.04 (3H, s), −0.02 (3H, s), 0.84 (9H, s), 1.47 (3H,s), 1.95-2.15 (2H, m), 3.54-3.63 (2H, m), 7.29 (1H, dd, J=6.1, 2.6 Hz),7.45-7.48 (2H, m).

-   The 6^(th) step: Toluene (66 ml) and water (33 ml) were added to    compound (55)(10.06 g) and stirred under ice cooling. After the    addition of potassium carbonate (11.13 g), thiophosgene (2.86 ml)    was added dropwise. After reacting for an hours, water was added,    extracted with chloroform and the organic layer was dried over    anhydrous sodium sulfate. The solvent was evaporated under reduced    pressure and the residue was purified with a silicagel column    chromatography to give compound (56)(9.43 g).

¹H-NMR (CDCl₃) δ: −0.03 (6H, s), 0.82 (9H, s), 1.80 (3H, s), 2.21-2.24(1H, m), 2.44-2.48 (1H, m), 3.57 (1H, ddd, J=12.0, 5.8, 4.8 Hz), 3.71(1H, ddd, J=12.0, 5.8, 4.8 Hz), 7.37 (1H, dd, J=7.5, 1.2 Hz), 7.48-7.58(2H, m).

-   The 7^(th) step: 28% Ammonia water (47 ml) was added to compound    (56)(9.43 g) dissolved in tetrahydrofuran (94 ml) stirred at room    temperature. After stirring for 16 hours, water was added, extracted    with ethyl acetate and the organic layer was dried over anhydrous    sodium sulfate. The solvent was evaporated under reduced pressure to    give compound (57)(6.35 g) as a crude product.-   The 8^(th) step: Acetic acid (1.09 g) and a 1.0 M solution of    tetrabutylammonium fluoride/tetrahydrofuran (18.20 ml) were added to    a solution of the compound (57)(6.35 g) obtained in the 7th step in    tetrahydrofuran (127 ml) stirred under ice cooling. After stirring    at room temperature for 3 hours, water and potassium carbonate were    added and extracted with ethyl acetate. The organic layer was dried    over anhydrous sodium sulfate, concentrated under reduced pressure    and the residue was purified with a silicagel column chromatography    to give compound (58)(4.47 g).

¹H-NMR (CDCl₃) δ: 1.85 (3H, s), 2.27-2.31 (2H, br m), 3.73-3.83 (2H, m),5.86 (2H, br s), 7.43 (1H, d, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.61(1H, t, J=7.8 Hz), 7.81 (1H, br s).

-   The 9^(th) step: 1-Chloro-N,N,2-trimethyl-1-propenylamine (2.16 g)    was added to compound (58)(4.47 g) dissolved in dichloromethane    (89 ml) stirred under ice cooling. After stirring at room    temperature for 1.5 hours, water was added and extracted with    dichloromethane. The organic layer was dried over anhydrous sodium    sulfate, concentrated under reduced pressure and the residue was    purified with a silicagel column chromatography to give compound    (59)(2.91 g).

¹H-NMR (CDCl₃) δ: 1.53 (3H, s), 1.88 (1H, ddd, J=13.9, 10.1, 3.8 Hz),2.40 (1H, ddd, J=13.9, 6.6, 3.8 Hz), 2.71 (1H, ddd, J=13.9, 10.1, 3.8Hz), 2.95 (1H, tt, J=6.6, 3.8 Hz), 4.33 (2H, br s), 7.29 (11H, dd,J=7.5, 1.2 Hz), 7.41-7.50 (1H, m).

-   The 10^(th) step: A mixture of compound (59)(2.91 g), di-tert-butyl    dicarbonate (5.52 g), 4-dimethylaminopyridine (0.12 g) and    tetrahydrofuran (29 ml) was stirred at room temperature for 2.5    hours. The reaction solvent was evaporated under reduced pressure    and the residue was purified with a silicagel column chromatography    to give compound (60)(1.23 g).

¹H-NMR (CDCl₃) δ: 1.53 (23H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8,9.4, 3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.7, 1.8 Hz), 2.91 (1H, ddd,J=12.7, 3.7, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.2, 3.7 Hz), 7.89 (1H, t,J=2.1 Hz), 8.55-8.57 (2H, m).

-   The 11^(th) step: Compound (60)(3.30 g),    trisdibenzylideneacetonedipalladipalium (0.93 g),    dicyclohexylbiphenylphosphine (0.73 g) were dissolved in toluene (66    ml), stirred at room temperature, and a 1.6 M solution of lithium    hexamethyldisilazide in tetrahydrofuran (12.7 ml) was added therein.    The reaction solution was warmed up to 80° C. and stirred for 8    hours, then, it was cooled in ice and diethyl ether and a 1 N    solution of hydrochloric acid were added. After stirring for 5    minutes, it was neutralized by the addition of a saturated aqueous    solution of sodium carbonate and extracted with ethyl acetate. The    organic layer was dried over anhydrous sodium sulfate, concentrated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (61)(1.55 g).

¹H-NMR (CDCl₃) δ: 1.61 (3H, s), 1.74-1.80 (1H, m), 1.96-2.11 (1H, m),2.64-2.82 (2H, m), 4.41 (2H, br s), 6.39 (1H, dd, J=8.1, 0.6 Hz), 6.71(1H, dd, J=8.1, 0.6 Hz), 7.42 (1H, t, J=8.1 Hz).

Reference Example 8

-   The 1^(st) step: Compound (63)(3.31 g) prepared in the same manner    as Reference Example 6 and 7 described above was dissolved in    dichloromethane (16.5 ml), bis(2,4-dimethoxybenzyl)amine (4.45 g)    was added and the solvent was evaporated under reduced pressure    after stirring at room temperature for an hour and standing for 15    hours. The residue was purified with silicagel chromatography to    give compound (63)(5.77 g).

¹H-NMR (CDCl₃): −0.10 (3H, s), −0.07 (3H, s), 0.77 (9H, s), 1.93 (3H,s), 2.08-2.27 (1H, m), 3.06-3.28 (1H, m), 3.38 (1H, ddd, J=10.8, 6.8,6.8 Hz), 3.55 (1H, ddd, J=10.8, 6.8, 6.8 Hz), 3.78 (6H, s), 3.79 (6H,s), 4.81-5.05 (1H, br), 6.43-6.50 (4H, m), 7.07 (1H, d, J=1.9 Hz), 7.17(2H, d, J=7.3 Hz), 8.05-8.16 (2H, m).

-   The 2^(nd) step: Compound (63)(5.77 g) was dissolved in    tetrahydrofuran (60 ml) and acetic acid (1.01 g) and 1M    tetrabutylammonium fluoride/tetrahydrofuran-solution (15 ml) were    added and the mixture was stirred at room temperature for 150    minutes. Water was added, extracted with ethyl acetate and the    organic layer was dried over anhydrous sodium sulfate. The solvent    was evaporated under reduced pressure and the residue was purified    with a silicagel chromatography to give compound (64)(3.94 g).

¹H-NMR (CDCl₃): 1.99 (3H, s), 1.91-2.02 (1H, m), 3.10 (1H, ddd, J=14.6,6.6, 5.2), 3.36-3.51 (2H, m), 3.78 (6H, s), 3.80 (6H, s), 4.58 (2H, d,J=15.8 Hz), 4.72 (2H, d, J=15.8 Hz), 6.43-6.51 (4H, m), 7.12 (1H, dd,J=5.3, 2.0 Hz), 7.18-7.29 (3H, m), 8.20 (1H, dd, J=5.3, 0.6 Hz),8.28-8.31 (1H, br).

-   The 3^(rd) step: Compound (64)(3.94 g) was dissolved in    dichloromethane (20 ml) and    1-chloro-N,N′,2-trimethyl-1-propenylamine (1.86 ml) was added under    ice cooling with stirring. After stirring at room temperature for 2    hours, water was added, extracted with chloroform and the organic    layer was dried over anhydrous sodium sulfate. The solvent was    evaporated under reduced pressure and the residue was purified with    a silicagel column chromatography to give a compound (65)(3.41 g).

¹H-NMR (CDCl₃): 1.49 (3H, s), 1.99 (1H, ddd, J=13.3, 7.6, 3.2 Hz), 2.31(1H, ddd, J=13.3, 8.6, 3.7), 2.78 (1H, ddd, J=12.2, 8.6, 3.2 Hz), 3.04(1H, ddd, J=12.2, 7.6, 3.7 Hz), 3.77 (6H, s), 3.79 (6H, s), 4.60 (2H, d,J=15.8 Hz), 4.76 (2H, d, J=15.8 Hz), 6.45-6.52 (4H, m), 7.08 (1H, dd,J=5.3, 2.1 Hz), 7.17-7.27 (3H, m), 8.40 (1H, dd, J=5.3, 0.5 Hz).

Reference Example 9

-   The 1^(st) step: Compound (66)(4.72 g) derived by a conventional    method from an intermediate prepared in the same manner as the    compound (27) described above was dissolved in tetrahydrofuran    (150 ml) and a diethylether solution of methyl magnesium bromide    (3M, 37 ml) was added dropwise with stirring under ice cooling in a    nitrogen stream for 12 minutes. After stirring 3 hours, a saturated    aqueous solution of ammonium chloride (190 ml) was added dropwise,    extracted with ethyl acetate, the organic layer was washed with    saturated brine and dried over anhydrous sodium sulfate. The solvent    was evaporated under reduced pressure and the residue was purified    with a silicagel column chromatography to give a compound (67)(2.11    g).

¹H-NMR (DMSO-d₆): 0.75 (3H, s), 1.09 (3H, s), 1.21 (9H, s), 1.79 (3H,s), 2.06 (1H, m), 2.29 (11H, m), 4.97 (1H, s), 6.57 (1H, s), 7.17 (1H,dd, J=8.7, 12.0 Hz), 7.48-7.53 (1H, m), 7.99-8.03 (1H, m), 11.26 (1H,bs).

-   The 2^(nd) step: Compound (67)(2.11 g) was dissolved in methanol    (7.8 ml) and hydrochloric acid-methanol solution (5-100%)(15.6 ml)    was added with stirring at room temperature, and the mixture was    stirred for 1.5 hours. Then the reaction solution was poured into    ice water and ethyl acetate (100 ml), a saturated aqueous solution    of sodium bicarbonate (50 ml) was added and extracted with ethyl    acetate. The aqueous layer was further extracted with ethyl acetate    (50 ml), organic layers were combined, washed with saturated brine    and dried over anhydrous sodium sulfate. The solvent was evaporated    under reduced pressure and the residue was crystallized from    n-hexane to give compound (68)(1.42 g).

¹H-NMR (DMSO-d₆): 0.65 (3H, s), 1.10 (3H, s), 1.43 (3H, s), 1.85 (1H, d.J=14.4 Hz), 2.17 (1H, dd, J=1.5, 14.4 Hz), 7.12 (1H, dd, J=2.7, 12.0Hz), 7.60-7.64 (1H, m), 7.90 (1H, dd, J=2.7, 7.5 Hz), 11.35 (1H, bs).

-   The 3^(rd) step: Toluene (9.6 ml) and water (4.8 ml) were added to    compound (68)(1.42 g) and suspended, potassium carbonate (2.13 g)    was added with stirring under ice cooling and 2 minutes later    thiophosgene (0.51 ml) was added at once and the stirring was    continued. The temperature was back to room temperature 40 minutes    later, toluene (40 ml) and water were added and extracted an hour    later. The aqueous layer was further extracted with toluene, organic    layers were combined, washed with saturated brine and dried over    anhydrous sodium sulfate. The solvent was evaporated under reduced    pressure to give a crude product (69)(2.02 g).-   The 4^(th) step: Tetrahydrofuran (17 ml) was added to    triphenylphosphine (1.735 g) and N-chlorosuccinimide (833 mg),    suspended in a nitrogen stream and stirred at room temperature for    10 minutes. A tetrahydrofuran (21 ml) solution of the crude product    (69)(2.02 g) was added dropwise using a dropping funnel for 2    minutes. After stirring for 6 hours, the mixture was left stand at    room temperature overnight. The solvent was evaporated under reduced    pressure and the residue was purified with a silicagel column    chromatography to give a compound (70)(828 mg).

¹H-NMR (DMSO-d₆): 1.54 (3H, s), 1.86 (3H, s), 2.81 (1H, d, J=13.8 Hz),2.92 (1H, d. J=13.8 Hz), 4.73 (1H, s), 4.85 (1H, m), 7.28-7.35 (1H, m),7.77-7.82 (2H, m), 11.39 (1H, bs).

-   The 5^(th) step: Compound (70)(828 mg) was dissolved in    tetrahydrofuran (4 ml), conc. ammonia water (28%)(4 ml) was added    with stirring under ice cooling and the temperature was back to room    temperature after stirring for 5 minutes. After 25 hours, the    reaction mixture was poured into ice water and extracted with ethyl    acetate (50 ml). The organic layer was washed with saturated brine    and dried over anhydrous sodium sulfate. The solvent was evaporated    under reduced pressure and the residue was purified with a silicagel    chromatography to give a compound (71)(260 mg).

¹H-NMR (DMSO-d₆): 1.47 (3H, bs), 1.66 (3H, bs), 2.58 (1H, d, J=12.3 Hz),4.71 (1H, s), 4.87 (3H, bs), 6.42 (1H, bs), 6.51 (1H, dd, J=2.7, 7.2Hz), 6.75 (2H, bs), 7.54 (1H, bs).

-   The 6^(th) step: Compound (71)(245 mg) was dissolved in chilled    conc. sulfuric acid (4.9 ml) and stirred under ice cooling for 2    hours. The reaction solution was poured into ice water with stirring    and pH was adjusted to 2-3 by the addition of a 5N aqueous solution    of sodium hydroxide. Ethyl acetate (100 ml) and an aqueous solution    of potassium carbonate were added and extracted under alkaline    condition. The alkaline layer was further extracted with ethyl    acetate (50 ml). Organic layers were combined, washed with saturated    brine (50 ml) and dried over anhydrous sodium sulfate. The solvent    was evaporated under reduced pressure and the residue was purified    with a silicagel column chromatography to give a compound (72)(101    mg) as a crystal.

¹H-NMR (DMSO-d₆): 0.83 (3H, s), 1.27 (3H, s), 1.44 (3H, s), 1.54 (1H, d,J=14.1 Hz), 2.45 (1H, d, J=14.1 Hz), 4.79 (2H, s), 5.89 (2H, bs),6.32-6.37 (1H, m), 6.58 (1H, dd, J=2.7, 7.2 Hz), 6.72 (1H, dd, J=8.7,12.3 Hz).

Reference Example 10

-   The 1^(st) step: Ethyl bromodifluoroacetate (0.77 ml) was added to a    suspension of zinc dust (392 mg) in tetrahydrofuran (4 ml) with    stirring in a nitrogen stream at room temperature, stirred for 15    minutes, ethyl bromodifluoroacetate (0.29 ml) was added, stirred for    30 minutes to prepare a solution of ethyl bromozincdifluoroacetate.    This solution was added to a solution of compound (73) in    tetrahydrofuran (3 ml) in a nitrogen stream and stirred for 8 hours.    3% Ammonia water was added to the reaction mixture with stirring    under ice cooling, extracted with ethyl acetate, the organic layer    was washed with saturated brine and dried over anhydrous magnesium    sulfate. The solvent was evaporated under reduced pressure and the    residue was purified with a silicagel column chromatography to give    a compound (74)(696 mg).

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.2 Hz), 1.18 (9H, s), 2.00 (3H,brs), 4.24 (2H, q, J=7.2 Hz), 5.56 (1H, brs), 7.56 (dd, J=9.0, 11.7 Hz),8.36 (1H, m), 8.49 (1H, dd, J=3.0, 6.6 Hz).

-   The 2^(nd) step: Compound (74)(670 mg) was dissolved in    tetrahydrofuran (6.7 ml) and lithium borohydride (71 mg) was added    in a nitrogen stream with stirring under ice cooling. After stirring    for 30 minutes, acetic acid (198 mg) and ice water were added to the    reaction mixture, extracted with ethyl acetate, the organic layer    was washed with brine and dried over anhydrous magnesium sulfate.    The solvent was evaporated under reduced pressure and the residue    was purified with a silicagel column chromatography to give a    compound (75)(401 mg).

¹H-NMR (DMSO-d₆) δ: 1.20 (9H, s), 2.00 (3H, d, J=3.6 Hz), 3.80 (1H, m),4.00 (1H, m), 5.99 (1H, s), 6.34 (1H, t, J=5.7 Hz), 7.53 (1H, dd, J=9.0,12.0 Hz), 8.31 (1H, m), 8.50 (1H, dd, J=2.7, 6.6 Hz).

-   The 3^(rd) step: Compound (75)(394 mg) was dissolved in methanol (3    ml), and 4N—HCl/1,4-dioxane (1.35 ml) was added with stirring under    ice cooling. After stirring for minutes, the mixture was stirred at    room temperature for 1.5 hours. Ice water was added to the reaction    solution and washed with ethyl acetate. The aqueous layer was made    alkaline by the addition of a 2M aqueous solution of potassium    carbonate and extracted with ethyl acetate. The organic layer was    dried over anhydrous magnesium sulfate, the solvent was evaporated    under reduced pressure to give compound (76)(293 mg).

¹H-NMR (DMSO-d₆) δ: 1.62 (3H, d, J=2.7 Hz), 2.62 (2H, brs), 3.65-3.83(2H, m), 5.31 (1H, brt), 7.44 (1H, dd, J=9.0, 11.4 Hz), 8.23 (1H, m),8.59 (1H, dd, J=3.0, 6.9 Hz).

-   The 4^(th) step: Compound (76)(266 mg) was dissolved in acetone    (3 ml) and benzoyl isothiocyanate (164 mg) was added in a nitrogen    stream with stirring under ice cooling. After stirring for an hour,    the mixture was stirred at room temperature for an hour. The    reaction solution was concentrated under reduced pressure and the    residue was purified with a silicagel column chromatography to give    a compound (77)(353 mg).

¹H-NMR (DMSO-d₆) δ: 2.30 (3H, brs), 3.65-3.96 (2H, m), 5.90 (1H, brt),7.42-7.68 (4H, m), 7.93-7.96 (2H, m), 8.17-8.33 (2H, m), 11.42 (1H,brs), 12.31 (1H, brs).

-   The 5^(th) step: Compound (77)(348 rig) was dissolved in    dichloromethane (4 ml) and 1-chloro-N,N-2-trimethyl-1-propenylamine    (131 mg) was added in a nitrogen stream with stirring under ice    cooling. After stirring for 15 hours at room temperature, ice water    was added and neutralized by the addition of potassium carbonate. It    was extracted with ethyl acetate, washed with brine and dried over    anhydrous magnesium sulfate. The solvent was evaporated under    reduced pressure and the residue was purified with a silicagel    column chromatography to give a compound (78)(308 mg).

¹H-NMR (CDCl₃) δ: 1.89 (3H, d, J=3.0 Hz), 3.17 (1H, ddd, J=8.4, 10.2,13.2 Hz), 3.51 (1H, ddd, J=6.0, 13.2, 19.2 Hz), 7.23 (1H, dd, J=9.0,10.8 Hz), 7.49-7.64 (3H, m), 7.91 (2H, d, J=7.2 Hz), 8.24 (1H, m), 8.43(1H, dd, J=3.0, 6.6 Hz), 8.57 (1H, br).

-   The 6^(th) step: Compound (78)(297 mg) was dissolved in ethanol (4    ml), water (1.5 ml) and conc. hydrochloric acid (1.5 ml) were added    and the mixture was stirred at 90° C. for 2.5 hours. Water was added    to the reaction solution, washed with ethyl acetate and the aqueous    layer was made alkaline by the addition of a 2M aqueous solution of    potassium carbonate. It was extracted with ethyl acetate, washed    with brine and the organic layer was dried over anhydrous magnesium    sulfate. The solvent was evaporated under reduced pressure and the    residue was purified with a silicagel column chromatography to give    a compound (79)(89 mg).

¹H-NMR (CDCl₃) δ: 1.85 (3H, d, J=3.6 Hz), 3.15 (1H, ddd, J=8.7, 10.5,12.9 Hz), 3.50 (1H, ddd, J=5.4, 12.9, 18.3 Hz), 4.51 (2H, brs), 7.19(1H, dd, J=9.0, 11.1 Hz), 8.20 (1H, ddd, J=3.0, 6.9, 9.0 Hz), 8.54 (1H,dd, J=3.0, 6.9 Hz).

-   The 7^(th) step: Compound (79)(82 mg) was dissolved in    dichloromethane (1 ml), di-tert-butyldicarbonate (176 mg) and    4-dimethylaminopyridine (4 mg) were added and the mixture was    stirred at room temperature for 30 minutes. The reaction solution    was concentrated under reduced pressure and the residue was purified    with a silicagel column chromatography to give a compound (80)(101    mg).

¹H-NMR (CDCl₃) δ: 1.56 (18H, S), 1.90 (3H, d, J=3.6 Hz), 3.27 (1H, ddd,J=6.6, 9.3, 12.9 Hz), 3.69 (1H, ddd, J=4.2, 12.9, 17.4 Hz), 7.23 (1H,dd. J=9.0, 12.0 Hz), 8.24 (1H, ddd, J=3.0, 9.0, 12.0 Hz), 8.41 (1H, ddd,J=2.4, 3.0, 6.0 Hz).

-   The 8^(th) step: Compound (80)(4.76 g) was dissolved in methanol (70    ml), 10% Pd—C(containing 50% water)(2.38 g) was added and the    mixture was stirred in a hydrogen atmosphere for 20 hours. The    catalyst was filtered off, the solvent was evaporated under reduced    pressure to give compound (81)(4.43 g)

¹H-NMR (CDCl₃) δ: 1.54 (18H, S), 1.85 (3H, d, J=2.4 Hz), 3.24 (1H, m),3.44 (1H, m), 3.53 (2H, brs), 6.61 (1H, m), 6.82-6.89 (2H, m).

Reference Example 11

-   The 1^(st) step: A solution of 2.0M lithium    diisopropylamide/n-heptane/ethyl benzene (182 ml) in tetrahydrofuran    (150 ml) was cooled in a dry ice-acetone bath, and a solution of    methyl isobutyrate (27.17 g) in tetrahydrofuran (90 ml) was added    dropwise with stirring. After stirring for 40 minutes, a solution of    chlorotitanium triisopropoxide (97.07 g) in tetrahydrofuran (300 ml)    was added dropwise. After stirring for 15 minutes, a solution of    compound (86)(25.39 g) in tetrahydrofuran (150 ml) was added    dropwise. After the reaction for 2.5 hours, the reaction mixture was    poured portionwise into an aqueous solution of ammonium chloride    stirred under ice cooling and the formed insoluble materials were    filtered. It was extracted with ethyl acetate, and the organic layer    was dried over anhydrous magnesium sulfate. The solvent was    evaporated under reduced pressure and the residue was purified with    a silicagel column chromatography to give a compound (87)(23.98 g).

¹H-NMR (CDCl₃) δ: 1.12 (3H, s), 1.22 (3H, s), 1.35 (9H, s), 1.99 (3H, d,J=5.8 Hz), 3.75 (3H, s), 5.65 (1H, s), 7.20 (0H, dd, J=11.5, 8.9 Hz),8.18-8.21 (1H, m), 8.45 (1H, dd, J=6.9, 2.9 Hz).

-   The 2^(nd) step: Compound (87)(391 mg) was dissolved in    tetrahydrofuran (4 ml) and lithium borohydride (44 mg) was added in    3 minutes in a nitrogen stream with stirring at room temperature.    After stirring for 2 hours, lithium borohydride (22 mg) was further    added and the stirring was continued. After stirring for 2 hours, a    saturated aqueous solution of ammonium chloride was slowly added to    the reaction solution with stirring under ice cooling, extracted    with ethyl acetate 5 minutes later, the organic layer was washed    with saturated brine and dried over anhydrous sodium sulfate. The    solvent was evaporated under reduced pressure and the residue was    purified with a silicagel column chromatography to give a compound    (88)(175 mg).

¹H-NMR (DMSO-d₆) δ: 0.65 (3H, d, J=1.8 Hz), 0.93 (3H, s), 1.22 (9H, s),1.93 (3H, d, J=6.6 Hz), 3.24 (1H, d, J=8.4 Hz), 3.74 (1H, d, J=8.4 Hz),5.96 (1H, bs), 6.75 (1H, s), 7.47 (1H, dd, J=9.0, 12.0 Hz), 8.23 (1H,ddd, J=3.0, 3.0, 9.0 Hz), 8.39 (1H, dd, J=3.0, 6.9 Hz).

-   The 3^(rd) step: Compound (88)(331 mg) was dissolved in methanol    (1.5 ml), and a hydrogen chloride-methanol solution (5-10%)(3 ml)    was added with stirring at room temperature. After stirring for 1.5    hours, the reaction solvent was evaporated under reduced pressure.    The residue was dissolved in ethyl acetate-methanol (9:1), poured    into ice water, and a saturated aqueous solution of sodium    bicarbonate (4 ml) was added, extracted, washed with saturated brine    and the organic layer was dried over anhydrous sodium sulfate. The    solvent was evaporated under reduced pressure and the powder    obtained by the addition of n-hexane to the solid was filtered to    give a compound (89)(207 mg).

1H-NMR (D{dot over (M)}SO-d₆) δ: 0.80 (6H, s), 1.59 (3H, d, J=4.5 Hz),3.16 (1H, d, J=10.8 Hz), 7.38 (1H, dd, J=9.0, 12.0 Hz), 8.17 (1H, ddd,J=3.0, 3.0, 9.0 Hz), 8.64 (1H, dd, J=3.0, 6.9 Hz)

-   The 4^(th) step: Compound (89)(150 mg) was dissolved in acetone    (3 ml) and benzoyl isothiocyanate (0.079 ml) was added in a nitrogen    stream with stirring under ice cooling. After stirring for 2 hours,    the reaction solvent was evaporated under reduced pressure and the    residue was purified with a silicagel column chromatography to give    a compound (90)(236 mg).

LCMS: 420 m/z[M+H]⁺

-   The 5^(th) step: Compound (90)(233 mg) was dissolved in    dichloromethane (4 ml) and chloropropenylamine (0.081 ml) was added    at once in a nitrogen stream with stirring at room temperature.    After stirring for 23 hours, the reaction solution was poured into    ice water, extracted with ethyl acetate, washed with saturated brine    and the organic layer was dried over anhydrous sodium sulfate. The    solvent was evaporated under reduced pressure and the residue was    purified with a silicagel column chromatography to give a compound    (91)(128 mg).

¹H-NMR (DMSO-d) δ: 0.83 (3H, s), 1.12 (3H, s), 1.72 (3H, s), 2.69 (1H,d, J=13.2 Hz), 2.90-3.10 (1H, m), 7.44-7.58 (4H, m), 8.00 (2H, d J=7.5Hz), 8.23-8.35 (2H, m), 10.75 (1H, bs).

-   The 6^(th) step: Compound (91)(20 mg) was suspended in 99.5% ethanol    (0.4 ml), 6N hydrochloric acid (0.2 ml) was added and the mixture    was stirred in a oil bath heated to 90° C. After stirring for 17    hours, the reaction solution was poured into water, and extracted    with ethyl acetate. The aqueous layer was made alkaline by the    addition of a saturated aqueous solution of potassium carbonate    (pH=11), extracted with ethyl acetate, washed with saturated brine    and the organic layer was dried over anhydrous sodium sulfate. The    solvent was evaporated under reduced pressure to give compound    (92)(14 mg).

¹H-NMR (DMSO-d₆): 0.72 (3H, s), 1.00 (3H, d, J=3.6 Hz), 1.54 (3H, d,J=4.8 Hz), 2.61 (1H, d, J=12.3 Hz), 3.09 (1H, d, J=12.3 Hz), 5.98 (2H,s), 7.41 (1H, dd, J=9.0, 11.7 Hz), 8.16-8.21 (1H, m), 8.42 (1H, dd,J=3.0, 6.9 Hz).

-   The 7^(th) step: Compound (92)(12 mg) was dissolved in    dichloromethane (0.1 ml) and a    di-tert-butyldicarbonate-dichloromethane solution (0.0966M, 1.2 ml)    was added with stirring at room temperature. After stirring for 2    hours, the reaction solvent was evaporated under reduced pressure    and the residue was purified with a silicagel column chromatography    to give a compound (93)(15 mg).

¹H-NMR (DMSO-d) δ: 0.70 (3H, s), 1.02 (3H, s), 1.43 (9H, s), 1.56 (3H,bs), 2.61 (1H, d, J=12.9 Hz), 3.16 (1H, m), 7.45 (11H, dd, J=9.0, 11.4Hz), 8.20-8.24 (1H, m), 8.35 (1H, m), 9.87 (1H, bs).

-   The 8^(th) step: Methanol (4.1 ml) was added to compound (93×823    mg), suspended, and 10% Pd—C(50% wet)(412 mg) was added. A catalytic    reduction was carried out at normal pressure, and methanol (8.2 ml)    was added when a solid was precipitated and the reduction was    further continued. After 23 hours, the catalyst was filtered through    a Celite pad, washed with warm methanol, and the washings were    combined. The solvent was evaporated under reduced pressure and the    powder precipitated by the addition of diisopropylether to the    residue was filtered to give compound (94)(638 mg).

¹H-NMR (DMSO-d₆) δ: 0.87 (3H, bs), 1.06 (3H, bs), 1.39 (9H, s), 1.57(3H, bs), 2.66-2.72 (2H, m), 4.97 (2H, bs), 6.45-6.47 (2H, m), 6.78 (1H,m), 9.65 (1H, bs).

Reference Example 12

-   The 1^(st) step: 3-(Trifluoromethyl)-1H-pyrazole (591 mg) was    dissolved in dimethylformamide (7 ml), potassium carbonate (601 mg)    and compound (104×500 mg) were added thereto and stirred at room    temperature overnight. The reaction was quenched by an addition of    water. The insoluble materials were filtered and washed with    diisopropylether. The resulted solid was dried under reduced    pressure to give compound (105)(644 mg).

¹H-NMR (CDCl₃) δ: 4.08 (3H, s), 6.81 (1K d, J=2.5 Hz), 8.65 (1H, s),9.14 (1H, s), 9.45 (1H, s).

-   The 2^(nd) step: Compound (105)(640 mg) was added to a mixed solvent    of water-methanol (6 ml, 1:1), lithium hydroxide (84 mg) was added    and the mixture was stirred at room temperature for 4 hours. The    reaction solution was acidified by the addition of 2N hydrochloric    acid, the insoluble materials were filtered off and washed with    diisopropylether. The resulted solid was dried under reduced    pressure to give compound (106)(343 mg).

¹H-NMR (DMSO-d₆) δ: 7.20 (1H, d, J=2.5 Hz), 8.93 (1H, s), 9.12 (1H, s),9.33 (1H, s).

Reference Example 13

-   The 1^(st) step: A mixture of compound (107)(1000 mg), dioxane (2    ml), and 28% ammonia water (2 ml) was stirred at 50° C. for 19    hours. The reaction solution was concentrated under reduced    pressure. Water was added to the residue, extracted with ethyl    acetate and dried over anhydrous magnesium sulfate. The solvent was    evaporated under reduced pressure and the residue was purified with    a silicagel column chromatography to give a compound (108)(476 mg).

¹H-NMR (CDCl₃) δ: 1.63 (9H, s), 5.04 (2H, br s), 8.03 (1H, s), 8.69 (1H,s).

-   The 2^(nd) step: 3-Bromo-2-oxopropanoic acid ethyl ester (1582 mg)    was added to compound (108)(475 mg) in dimethoxyethane (4 ml) and    the mixture was stirred at 75° C. for 2.5 hours. The reaction    solution was diluted with diisopropylether, the insoluble materials    were filtered, washed with diisopropylether and hexane, and dried    under reduced pressure. The residue was stirred in tert-butyl    alcohol (7.5 ml) at 95° C. for 2 hours. The solvent was evaporated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (109)(709 mg).

¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J=7.1 Hz), 1.66 (9H, s), 4.50 (2H, q,J=7.1 Hz), 8.35 (1H, s), 8.89 (1H, s), 9.24 (1H, s).

-   The 3^(rd) step: A mixture of compound (09)(270 mg), dioxane (3 ml)    and 28% ammonia water (2.5 ml) was stirred in a pressure bottle at    50° C. for 6 hours. The reaction solution was concentrated under    reduced pressure to give a crude product of compound (110)(249 mg).

¹H-NMR of the crude product (CDCl₃) δ: 1.67 (9H, s), 5.79 (1H, br s),8.35 (1H, s), 8.90 (1H, s), 9.15 (1H, s).

-   The 4^(th) step: 2,2,2-Trichloroacetyl chloride (253 mg) was added    at 0° C. to a mixture of compound (10)(146 mg), triethylamine (282    mg) and dimethylaminopyridine (6.8 mg) in tetrahydrofuran (9 ml),    and the mixture was stirred at room temperature for 2 hours. The    reaction solution was diluted with ethyl acetate and the reaction    was quenched by the addition of a saturated aqueous solution of    sodium bicarbonate. It was extracted with ethyl acetate, dried over    anhydrous magnesium sulfate and the solvent was evaporated under    reduced pressure to give compound (111)(99 mg) as a crude product.-   The 5^(th) step: Compound (111)(95 mg) was dissolved in chloroform    (3 ml), trifluoroacetic acid (1330 mg) was added and the mixture was    stirred at room temperature for 4 hours. The reaction solution was    concentrated under reduced pressure to give a crude product. The    residue was suspended with ethyl acetate and diisopropylether and    the insoluble materials were filtered and washed with    diisopropylether. The residue was dried under reduced pressure to    give a composition including compound (112).

Reference Example 14

-   The 1^(st) step: A 2.6M n-butyl lithium/hexane solution (9.38 ml)    was added dropwise for 10 minutes to diisopropylamine (2.75 g)    dissolved in tetrahydrofuran (25 ml) under stirring in a dry    ice/acetone bath. After stirring in a ice bath for 10 minutes and in    a dry ice/acetone bath for 10 minutes, tert-butyl    α-benzoyloxyacetate (5.21 g) dissolved in tetrahydrofuran (25 ml)    was added dropwise for 30 minutes. After stirring for 40 minutes,    chlorotitaniumtriisopropoxide (6.60 g) dissolved in tetrahydrofuran    (50 ml) was added dropwise. After stirring for 30 minutes, compound    (73)(2.68 g) dissolved in tetrahydrofuran (50 ml) was added dropwise    for 10 minutes and stirred for 90 minutes. A suspension of ammonium    chloride (7.52 g) in tetrahydrofuran-water (1:1, 40 ml) was stirred    at room temperature, and the reaction mixture was added thereto at    once and the precipitated insoluble materials were filtered. The    filtrate was extracted with ethyl acetate, the organic layer was    dried over anhydrous sodium sulfate. The solvent was evaporated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (4.49 g).

¹H-NMR (CDCl₃) δ: 1.14 (3.6H, s), 1.22 (3.6H, s), 1.27 (5.4H, s), 1.39(5.4H, s), 1.96 (1.2H, s), 1.99 (1.8H, s), 4.31 (0.4H, s), 4.34 (0.6H,d, J=11.6 Hz), 4.41 (0.4H, d, J=11.6 Hz), 4.45 (0.6H, s), 4.56 (0.4H,s), 4.68 (0.6H, d, J=11.6 Hz), 4.81 (0.4H, d, J=11.6 Hz), 5.01 (0.6H,s), 7.06-7.38 (6H, m), 8.18 (0.6H, d, J=8.8 Hz), 8.24 (0.4H, d, J=9.1Hz), 8.42-8.47 (1H, m).

-   The 2^(nd) step: Compound (113)(4.49 g) was dissolved in    trifluoroacetic acid (44 ml), stirred at room temperature for an    hour and the solvent was evaporated under reduced pressure. The    resulted residue was dissolved in 10% hydrochloric acid-methanol (44    ml), stirred at room temperature overnight and the reaction solution    was concentrated under reduced pressure. The residue was dissolved    in tetrahydrofuran (22 ml) and a solution of    1M-borane-tetrahydrofuran complex in tetrahydrofuran (44.1 ml) was    added dropwise for 15 minutes under ice cooling, and the mixture was    stirred at room temperature for 2.5 hours. Water (50 ml) was added    therein with stirring under ice cooling, stirred for 15 minutes and    ethyl acetate (50 ml) and potassium carbonate (16 g) were added. It    was extracted with ethyl acetate and the organic layer was dried    over anhydrous sodium sulfate. The solvent was evaporated under    reduced pressure and the obtained compound (114)(3.27 g) was used in    the next step without purification.-   The 3^(rd) step: Benzoyl isothiocyanate (1.41 ml) was added to    compound (114)(3.27 g) in methylenechloride (16.5 ml), stirred at    room temperature for an hour and the solvent was evaporated under    reduced pressure. The residue was purified with a silicagel column    chromatography to give compound (115)(3.14 g).

¹H-NMR (CDCl₃) δ: 2.14 (1.35H, s), 2.21 (1.65H, s), 3.73-4.07 (3H, m),4.43 (0.55H, d, J=11.5 Hz), 4.63 (0.55H, d, J=11.5 Hz), 4.74 (0.45H, d,J=11.5 Hz), 4.78 (0.45H, d, J=11.5 Hz), 7.20-7.38 (4H, m), 7.43-7.51(2H, m), 7.56-7.63 (1H, m), 7.75-7.86 (2H, m), 8.08-8.17 (1H, m),8.24-8.34 (11H, m), 8.91-9.01 (1H, m), 11.81 (0.55H, s), 11.90 (0.45H,s).

-   The 4^(th) step: α-Chlorotetramethylenamine (1.67 ml) was added to    compound (115)(3.14 g) in methylenechloride (15.5 ml), stirred at    room temperature for 30 minutes and pH was adjusted to over 11 by    the addition of water (15 ml) and potassium carbonate. It was    extracted with chloroform and the organic layer was dried over    anhydrous sodium sulfate. The solvent was evaporated under reduced    pressure and the residue was purified with a silicagel column    chromatography to give compound (116)(2.66 g).

¹H-NMR (CDCl₃) δ: 1.58 (3bH, s), 1.81 (3aH, s), 2.76 (bH, dd, J=13.4,1.8 Hz), 3.09 (bH, dd, J=13.4, 6.1 Hz), 3.16 (aH, dd, J=13.8, 3.9 Hz),3.35 (aH, dd, J=13.8, 1.8 Hz), 4.21-4.25 (aH, m), 4.28 (aH, d, J=12.4Hz), 4.33-4.38 (bH, m), 4.49-4.56 (a+bH, m), 4.73 (bH, d, J=11.9 Hz),6.83-7.60 (10H, m), 7.91-8.23 (3H, m), 8.25-8.30 (bH, m), 8.74 (aH, m).

-   The 5^(th) step: Hydrazine monohydrate (0.73 ml) was added to    compound (116)(1.44 g) in ethanol (7.2 ml) and stirred at room    temperature for 2 hours. Water was added, extracted with ethyl    acetate and the organic layer was dried over anhydrous sodium    sulfate. The solvent was evaporated under reduced pressure and the    obtained compound (117)(1.14 g) was used in the next step without    purification.-   The 6th step: A solution of di-tert-butyl dicarbonate (1.65 g) in    methylenechloride (5.5 ml) and 4-dimethylaminopyridine (37 tug) were    added to compound (117)(1.14 g) in methylenechloride (5.5 ml) and    stirred at room temperature for an hour. The solvent was evaporated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (118)(1.52 g).

¹H-NMR (CDCl₃) δ: 1.47 (8.1H, s), 1.51 (9.9H, s), 1.53 (1.35H, s), 1.75(1.65H, s), 3.01-3.49 (2H, m), 3.81-3.86 (0.55H, m), 4.07-4.09 (0.45H,m), 4.17 (0.45H, d, J=12.1 Hz), 4.25 (0.55H, d, J=11.6 Hz), 4.41 (0.45H,d, J=12.1 Hz), 4.49 (0.55H, d, J=11.6 Hz), 6.73-6.78 (1H, m), 6.94-7.23(5H, m), 8.11-8.18 (1H, m), 8.22-8.27 (0.55H, m), 8.51-8.55 (0.45H, m).

-   The 7th step: 20 w/w % Palladium hydroxide supported by carbon (40    mg) was added to a solution of compound (118)(211.3 mg) in ethanol    (2 ml), stirred in a hydrogen atmosphere of 1 atom at room    temperature for 22 hours and filtered through a Celite pad. The    filtrate was concentrated under reduced pressure and the residue was    purified with a silicagel column chromatography to give compound    (119)(149.1 mg).

¹H-NMR (CDCl₃) δ: 1.46 (8.1H, s), 1.51 (9.9H, s), 1.54 (1.35H, s), 1.74(1.65H, s), 2.91 (0.55H, d, J=12.9 Hz), 3.02 (0.55H, dd, J=12.9, 6.3Hz), 3.15 (0.45H, dd, J=13.3, 3.0 Hz), 3.37-3.73 (2H, br), 3.43 (0.45H,d, J=13.3 Hz), 4.13-4.18 (1H, m), 4.22 (0.45H, d, J=11.9 Hz), 4.34(0.45H, d, J=11.9 Hz), 4.49 (0.55H, d. J=1.6 Hz), 4.59 (0.55H, d, J=11.6Hz), 6.45-6.61 (1H, m), 6.71-7.39 (7H, m).

Example 1 Preparation of Compound 46

Compound (34)(125 mg) and DMT-MM (162 mg) were suspended in methanol(1.2 ml), stirred at room temperature for 30 minutes and compound(33)(117 mg) was added therein. After stirring for 5 hours, the productwas isolated by a silicagel thin-layer chromatography to give theobjective compound (46)(13.5 mg).

¹H-NMR (DMSO-d₆) δ: 1.47 (3H, s), 1.81 (1H, d, J=11.6 Hz), 2.12 (1H,bs), 2.54-2.59 (1H, m), 2.97 (1H, bs), 3.28 (2H, d, 6.4 Hz), 3.52 (2H,d, 6.5 Hz), 3.88 (3H, s), 5.69 (2H, s), 7.09 (1H, dd, J=11.8, 6.8 Hz),7.50 (1H, s), 7.60 (1H, d, J=7.8 Hz), 7.67 (1H, s), 10.06 (1H, s).

Example 2 Preparation of Compound 86

-   The 1st step: Sodium hydride (302 mg) is added to DMF (3.0 ml) and    3-butene alcohol (3.0 ml) under ice cooling in a nitrogen    atmosphere. After stirring at room temperature for 1.0 hour,    compound (35)(300 mg) was added and stirred under heating at 65° C.    After 7 hours, the reaction solution was neutralized by the addition    of 2M hydrochloric acid and concentrated under reduced pressure.    Water was added to the resulted residue and filtered to give    compound (36)(87 mg, 23.7%).-   The 2^(nd) step: Compound (36)(65.8 mg) and compound (37)(50 mg)    were dissolved in methanol (2.0 ml), DMT-MM (93.7 mg) was added and    the mixture was stirred at room temperature. After 6 hours, the    solvent was evaporated under reduced pressure and the residue was    purified with a column chromatography using chloroform/methanol to    give compound (86)(40 mg, 44.5%).

¹H-NMR (DMSO-d₆) δ: 1.65 (3H, s), 2.03-2.09 (1H, m), 2.34-2.38 (1H, m),2.51-2.61 (2H, m), 3.10-3.13 (1H, m), 3.57 (2H, t, J=4.4 Hz), 4.45 (2H,t, J=6.4 Hz), 5.13 (2H, dd, J=29.1, 13.9 Hz), 5.83-5.92 (1H, m), 7.08(1H, d, J=7.8 Hz), 7.40 (1H, t, J=8.0 Hz), 7.84 (1H, s), 7.91 (1H, d,J=8.1 Hz), 8.36 (1H, s), 8.87 (1H, s), 10.56 (1H, s).

Example 3

A carboxylic acid, R—COOH corresponding to the objective compound (0.115mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride (0.106 mmol) were dissolved in methanol (0.4 ml) and stirred byshaking at room temperature for 1.5 hours. A solution of compound A(0.0884 mmol) in methanol (0.4 ml) was added and the mixture was stirredfor 8 hours. The reaction solvent was concentrated, dissolved in ethylacetate (1 ml) and dimethylsulfoxide (0.5 ml), a 2N aqueous solution ofsodium hydroxide (1 ml) was added and stirred by shaking for 2 hours.The organic layer was separated and concentrated to give a crude productof compound B. Trifluoroacetic acid (0.3 ml) was added and stirred byshaking at room temperature for 14 horns, dimethylsulfoxide (0.4 ml) wasadded and the product was purified with preparative LC/MS to give theobjective compound C.

Example 4 Preparation of Compound 668

-   The 1^(st) step: Compound (82)(506 mg) was dissolved in chloroform    (30.0 ml), an aqueous solution (10.0 ml) of sodium bicarbonate (851    mg) and thiophosgene (0.111 ml) were added and stirred under ice    cooling for 40 minutes. The organic layer was separated from the    reaction solution and dried over anhydrous sodium sulfate. The    solvent was evaporated under reduced pressure to give compound    (83)(457 mg).

¹H-NMR (DMSO-d) δ: 1.44 (9H, s), 1.51 (3H, s), 1.60 (1H, s), 2.17 (1H,s), 2.68 (1H, s), 3.05 (1H, s), 7.30 (1H, t, J=10.1 Hz), 7.42 (1H, s),7.58 (1H, s).

-   The 2^(nd) step: Compound (83)(240 mg) was dissolved in    methylenechloride (3.60 ml), pyridine-2-ylmethanamine (74.8 mg) and    triethylamine (0.192 ml) were added and the mixture was stirred at    room temperature for 40 minutes. The reaction solution was washed    with distilled water, the separated organic layer was dried over    anhydrous sodium sulfate. The solvent was evaporated under reduced    pressure to give compound (84)(210 mg).

¹H-NMR (DMSO-d₆) δ: 1.46 (9H, s), 1.65 (3H, s), 2.05 (2H, s), 2.57 (1H,s), 2.97 (1H, s), 4.86 (2H, s), 7.29 (3H, m), 7.40 (1H, d, J=7.3 Hz),7.66 (1H, s), 7.84 (1H, s), 8.27 (1H, s), 8.58 (1H, s), 9.96 (1H, s).

-   The 3^(rd) step: Compound (84)(95.1 ml) was dissolved in toluene    (1.50 ml), dicyclohexylcarbodiimide (40.1 mg) was added and the    mixture was stirred under irradiation of microwave at 100° C. for 20    minutes. The reaction solution was concentrated under reduced    pressure and the residue was purified with a column chromatography    to give compound (85)(38.0 mg).

¹H-NMR (DMSO-d₆) δ: 1.40 (9H, s), 1.61 (3H, s), 1.94 (2H, s), 2.57 (1H,s), 2.88 (1H, s), 6.55 (1H, d, J=6.3 Hz), 6.59 (1H, d, J=8.6 Hz), 7.07(1H, d, 8.6 Hz), 7.13 (2H, s), 7.29 (1H, s), 7.41 (1H, s, J=9.3H), 7.96(1H, d, J=6.8 Hz), 8.85 (1H, s).

-   The 4^(th) step: Compound (85)(38.0 mg) was dissolved in chloroform    (0.50 ml), trifluoroacetic acid (1.00 ml) was added and stirred at    room temperature for 2 hours. The reaction solution was extracted    with a mixture of chloroform/methanol and washed with an aqueous    solution of potassium carbonate and distilled water. The separated    organic layer was dried over anhydrous sodium sulfate and the    solvent was evaporated under reduced pressure. Diisopropylether was    added to the residue and the precipitated powder was filtered to    give compound (668)(9.39 mg).

¹H-NMR (DMSO-d₆) δ: 1.58 (3H, s), 1.90 (1H, s), 2.44 (1H, s), 2.62 (1H,t, J=9.7 Hz), 3.06 (1H, s), 6.57 (2H, td, J=15.0, 6.3 Hz), 7.05 (1H, dd,J=12.1, 10.6 Hz), 7.15 (1H, s), 7.24 (1H, d, J=5.3 Hz), 7.31 (1H, dd,J=7.7, 3.7 Hz), 7.42 (1H, d, J=8.8 Hz), 7.99 (1H, d, J=6.8 Hz), 8.85(1H, s).

Example 5 Preparation of Compound 674

-   The 1^(st) step: A solution of 2.0M lithium    diisopropylamide/n-heptane/ethylbenzene (172 ml) in tetrahydrofuran    (280 ml) was cooled in a dry ice/acetone bath and a solution of    tert-butyl cyclopropanecarboxylate (36.6 g) in tetrahydrofuran    (60 ml) was added dropwise with stirring. After stirring for an    hour, a solution of chlorotitanium triisopropoxide (92 g) in    tetrahydrofuran (190 ml) was added dropwise, stirred for 10 minutes    and a solution of compound (73)(24.56 g) in tetrahydrofuran (120 ml)    was added dropwise. After reaction for 2 hours, the reaction    solution was added portionwise to an aqueous solution of ammonium    chloride with stirring under ice cooling and the precipitated    insoluble materials were filtered. It was extracted with ethyl    acetate, the organic layer was dried over anhydrous sodium sulfate.    The solvent was evaporated under reduced pressure and the residue    was purified with a silicagel column chromatography to give compound    (95)(15.49 g).

¹H-NMR (CDCl₃) δ: 1.16-1.19 (2H, m), 1.24 (9H, s), 1.28-1.32 (2H, m),1.36 (9H, s), 1.46 (3H, s), 1.50-1.55 (2H, m), 1.64-1.72 (2H, m), 5.45(1H, s), 7.11-7.16 (1H, m), 8.11-8.16 (1H, m), 8.67 (1H, dd, J=6.9, 2.9Hz).

-   The 2^(nd) step: 2.0 M Hydrochloric acid/ethyl acetate (30 ml) was    added to compound (95)(2.48 g) and stirred at 65° C. for 5.5 hours.    Diisopropylether was added and the precipitated solid was filtered    to give a crude product of compound (96)(1.66 g).-   The 3^(rd) step: A solution of compound (96)(1.66 g) in    tetrahydrofuran (8.3 ml) was stirred under ice cooling and a    solution of 1M borane/tetrahydrofuran (21.8 ml) was added and the    mixture was stirred at room temperature for 2 hours and 45 minutes.    Ice and sodium bicarbonate were added, extracted with ethyl acetate    and the organic layer was dried over anhydrous magnesium sulfate.    The solvent was evaporated under reduced pressure to give a crude    product of compound (97)(1.36 g).-   The 4th step: A solution of compound (97)(1.36 g) in acetone (20 ml)    was stirred under ice cooling, a solution of benzoyl isothiocyanate    (0.92 g) in acetone (6 ml) was added and the mixture was stirred for    40 minutes. After the addition of water, the reaction solution was    extracted with ethyl acetate and the organic layer was dried over    anhydrous magnesium sulfate. The solvent was evaporated under    reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (98)(1.68 g).

¹H-NMR (CDCl₃) δ: 0.67-0.73 (3H, m), 0.84-0.88 (1H, m), 1.73 (1H, t,J=5.6 Hz), 2.29 (3H, d. J=2.0 Hz), 3.44 (1H, dd, J=12.2, 5.1 Hz), 3.82(1H, dd, J=12.2, 5.1 Hz), 7.14 (1H, dd, J=11.0, 9.0 Hz), 7.52 (2H, t,J=7.6 Hz), 7.63 (1H, t, J=7.6 Hz), 7.87 (2H, d, J=7.6 Hz), 8.17 (1H,ddd, J=9.0, 3.9, 2.9 Hz), 8.27 (1H, dd, J=6.8, 2.9 Hz), 8.82 (1H, s),11.75 (1H, s).

-   The 5^(th) step: Compound (98)(1.68 g) was dissolved in    dichloromethane (17 ml), stirred under ice cooling and    1-chloro-N,N,2-trimethyl-1-propenylamine (0.60 g) was added. After    stirring at room temperature for an hour, water was added, the    reaction solution was extracted with ethyl acetate and the organic    layer was dried over anhydrous magnesium sulfate. The solvent was    evaporated under reduced pressure and the residue was purified with    a silicagel column chromatography to give compound (99)(1.34 g).

¹H-NMR (CDCl₃) δ: 0.77-0.82 (1H, m), 0.95-1.07 (2H, m), 1.38-1.40 (1H,m), 1.52 (3H, d, J=1.1 Hz), 2.25 (1H, d, J=13.0 Hz), 3.05 (1H, d, J=13.0Hz), 7.27 (1H, dd, J=10.8, 8.9 Hz), 7.40-7.54 (3H, m), 8.18-8.27 (3H,m), 8.36 (1H, dd, J=6.7, 2.7 Hz).

-   The 6^(th) step: Hydrazine monohydrate (038 g) was added to a    solution of compound (99)(1.00 g) in ethanol (10 ml) under stirring    at room temperature. After stirring for 4 hours, it was stirred    under heating at 50° C. for 2 hours. The reaction solution was    concentrated under reduced pressure, water was added, and the    mixture was extracted with ethyl acetate and the organic layer was    dried over anhydrous magnesium sulfate. The solvent was evaporated    under reduced pressure to give compound (100)(0.69 g) as a crude    product.-   The 7^(th) step: A mixture of compound (100)(0.91 g),    di-tert-butyldicarbonate (1.55 g), 4-dimethylaminopyridine (0.04 g)    and tetrahydrofuran (9.1 ml) was stirred at room temperature for 1    hour and 15 minutes. Water was added, the reaction solution was    extracted with ethyl acetate and the organic layer was dried over    anhydrous magnesium sulfate. The solvent was evaporated under    reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (101)(1.28 g).

¹H-NMR (CDCl₃) δ: 0.37-0.41 (1H, m), 0.50-0.54 (1H, m), 0.68 (2H, t,J=7.7 Hz), 1.56 (18H, s), 1.78 (3H, d, J=4.0 Hz), 2.35 (1H, d, J=12.7Hz), 3.57 (1H, dd, J=12.7, 1.8 Hz), 7.12-7.21 (1H, m), 8.15 (1H, ddd,J=8.9, 3.9, 3.0 Hz), 8.39 (1H, dd, J=6.7, 3.0 Hz).

-   The 8^(th) step: Compound (101)(1.28 g) was dissolved in ethyl    acetate (13 ml), 10% Pd—C(0.64 g) was added and the mixture was    stirred at room temperature for 13 hours and 30 minutes. The    insoluble materials were filtered, the filtrate was concentrated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (102)(1.07 g).

¹H-NMR (CDCl₃) δ: 0.51-0.58 (2H, m), 0.81-0.86 (2H, m), 1.54 (18H, s),1.64 (3H, d, J=3.0 Hz), 2.60 (1H, d, J=12.4 Hz), 3.08 (1H, d, J=12.4Hz), 3.50 (2H, s), 6.51 (1H, ddd, J=8.6, 3.7, 3.0 Hz), 6.78-6.84 (2H,m), 7.18-7.21 (1H, m).

-   The 9^(th) step: A solution of 5-methylpyrazine-2-carboxylic acid    (59 mg) in N,N-dimethylformamide (1.5 ml) was stirred under ice    cooling, and    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo(4,5-b)pyridinium-3-oxide    hexafluorophosphate (196 mg) and triethylamine (61 mg) were added    and the mixture was stirred for 10 minutes. A solution of compound    (102)(200 mg) in N,N-dimethylformamide (3 ml) was added and the    mixture was stirred at room temperature for 4 hours. Water was    added, extracted with ethyl acetate and the organic layer was dried    over anhydrous sodium sulfate. The solvent was evaporated under    reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (103)(170 mg).-   The 10^(th) step: Compound (103)(170 mg) was dissolved in    dichloromethane (0.75 ml), stirred under ice cooling,    trifluoroacetic acid (0.75 ml) was added and the mixture was stirred    at room temperature for 3 hours. After concentration of the reaction    solution under reduced pressure, ice water was added, potassium    carbonate was added with stirring under ice cooling and extracted    with ethyl acetate. The organic layer was dried over anhydrous    sodium sulfate, the solvent was evaporated under reduced pressure    and ether/hexane was added to the residue. The precipitated solid    was filtered to give compound (674)(104 mg)

¹H-NMR (CDCl₃) δ: 0.53-0.59 (1H, m), 0.65-0.72 (1H, m), 0.85-0.91 (1H,m), 1.14-1.17 (1H, m), 1.47 (3H, d, J=2.0 Hz), 2.46 (1H, d, J=12.1 Hz),2.69 (3H, s), 2.89 (1H, dd, J=12.1, 1.3 Hz), 7.06 (1H, dd, J=11.5, 8.8Hz), 7.45 (1H, dd, J=6.8, 2.8 Hz), 7.94 (1H, ddd, J=8.8, 4.0, 2.8 Hz),8.44 (1H, d, J=1.3 Hz), 9.36 (1H, d, J=1.3 Hz), 9.60 (1H, s).

Example 6 Preparation of Compound 687

-   The 1^(st) step: Dichloromethane-trifluoroacetic acid (1:1, 1 ml)    was added to compound (120)(49 mg) and stirred at room temperature    for an hour. The reaction solution was concentrated under reduced    pressure, dimethyl sulfoxide-acetic anhydride (1:1, 1 ml) was added    to the residue, stirred at 50° C. for 1.5 hours and the solvent was    evaporated under reduced pressure. Hydrochloric acid (1M, 0.5 ml)    was added to the residue and stirred at 50° C. for 1 hours. A    saturated aqueous solution of sodium bicarbonate was added,    extracted with chloroform, and the organic layer was dried over    anhydrous sodium sulfate. The solvent was evaporated under reduced    pressure and the residue was purified with a silicagel column    chromatography. A mixture of chloroform-diethyl ether/ethyl acetate    was added and the precipitated slid was filtered to give compound    687(17 mg)

¹H-NMR (CDCl₃) δ: 1.78 (3H, s), 3.52 (1H, d, J=15.1 Hz), 3.73 (1H, d,15.1 Hz), 7.06 (1H, dd, J=10.4, 8.6 Hz), 7.73 (1H, dd, J=6.6, 1.3 Hz),7.82-7.86 (1H, m), 7.90 (1H, d, J=1.3 Hz), 8.48 (1H, d, J=1.3 Hz), 9.79(1H, s).

Example 7 Preparation of Compound 680, 681 and 682

-   The 1^(st) step: In a nitrogen atmosphere, diisopropylamine    (20.3 ml) and tetrahydrofuran (83.5 ml) were added and cooled to    −60° C. in an acetone/dry ice bath and a solution of 1.63M n-butyl    lithium/n-hexane was added dropwise while stirring was continued    until the temperature rose to 0° C. After stirring for 30 minutes,    the reaction solution was cooled to −60° C. in an acetone/dry ice    bath and a solution of tert-butyl acetate (16.8 ml) in    tetrahydrofuran (22.2 ml) was added dropwise with stirring. After    stirring for 45 minutes, a solution of compound (121×11.1 g) in    tetrahydrofuran (22.2 ml) was added dropwise. After 2.5 hours, a    saturated aqueous solution of ammonium chloride (100 ml) was stirred    under ice cooling and the reaction solution was poured portionwise    therein, extracted with ethyl acetate, and the organic layer was    dried over anhydrous magnesium sulfate. The solvent was evaporated    under reduced pressure and the residue was purified with a silicagel    column chromatography to give compound (122)(8.83 g).

¹H-NMR (CDCl₃) δ: 1.32 (17H, s), 1.93 (3H, s), 3.15 (1H, d, J=16.4 Hz),3.66 (1H, d, J=16.2 Hz), 5.50 (1H, s), 8.12 (1H, s), 8.36 (1H, s).

-   The 2^(nd) step: Lithium aluminium hydride (0.76 g) and    tetrahydrofuran (15 ml) were cooled in an ice-salt bath in a    nitrogen atmosphere and a solution of compound (122)(3.03 g) in    tetrahydrofuran (10 ml) was added dropwise with stirring. After    stirring for 15 minutes, acetone (4 ml) was added, insoluble    materials were filtered, extracted with ethyl acetate, and the    organic layer was washed with water and dried over anhydrous    magnesium sulfate. The solvent was evaporated under reduced pressure    to give compound (123)(2.30 g) as a crude product.

MS: 385 m/z[M+H]⁺

-   The 3^(rd) step: 10% Hydrochloric acid/methanol solution (30 ml) was    added to compound (123)(2.2 g) and stirred at room temperature for    1.5 hours. The solvent was evaporated under reduced pressure, the    residue was basified with a 2.0M aqueous solution of potassium    carbonate and extracted with ethyl acetate (100 ml). The organic    layer was washed with water, dried over anhydrous magnesium sulfate    and the solvent was evaporated under reduced pressure. Toluene    (30 ml) and water (15 ml) were added to the resulted crude product    (2.25 g), cooled in a ice bath and potassium carbonate (1.58 g) and    thiophosgene (0.656 ml) were added with stirring. After stirring at    room temperature for 30 minutes, the reaction solution was extracted    with toluene, the organic layer was washed with water and dried over    anhydrous magnesium sulfate. The solvent was evaporated under    reduced pressure, toluene (30 ml), thionyl chloride (1.25 ml) and    N,N-dimethylformamide (0.044 ml) were added to the resulted residue    and the mixture was stirred under heating at 80° C. for 1.5 hours.    The solvent was evaporated under reduced pressure, ice water was    added, extracted with ethyl acetate, and the organic layer was    washed with water and dried over anhydrous magnesium sulfate. The    solvent was evaporated under reduced pressure and the residue was    purified with a silicagel column chromatography to give compound    (124)(1.26 g).

¹H-NMR (CDCl₃) δ: 1.56 (3H, s), 2.54-2.64 (1H, m), 3.07-3.17 (1H, m),3.29-3.38 (1H, m), 3.50-3.57 (1H, m), 8.13 (1H, d, J=2.4 Hz), 8.44 (1H,d, J=2.4 Hz).

-   The 4^(th) step: Tetrahydrofuran (12.6 ml) and 28% ammonia water    (6.3 ml) were added to compound (124)(1.26 g) and stirred at room    temperature for 1.5 hours. The reaction solution was extracted with    ethyl acetate, the organic layer was washed with saturated brine and    dried over anhydrous sodium sulfate. The solvent was evaporated    under reduced pressure to give compound (125)(1.13 g) as a crude    product.

¹H-NMR (CDCl₃) δ: 1.70 (3H, s), 2.15-2.21 (1H, m), 2.52-2.58 (1H, m),2.70-2.77 (1H, m), 3.05-3.11 (1H, m), 4.44 (2H, br s), 8.12 (11H, s),8.34 (1H, s).

-   The 5^(th) step: Tetrahydrofuran (11.3 ml) and    di-tert-butyldicarbonate (0.89 ml) were added to compound    (125)(1.13 g) and stirred at room temperature for an hour.    Di-tert-butyldicarbonate (1.13 ml) and 4-dimethylaminopyridine    (0.086 g) were added and further stirred at room temperature for 2    hours. The solvent was evaporated under reduced pressure and the    residue was purified with a silicagel column chromatography to give    compound (126)(1.59 g).

¹H-NMR (CDCl₃) δ: 1.53 (18H, s), 1.73 (3H, s), 1.90-1.97 (1H, m),2.63-2.69 (1H, m), 2.93-2.99 (1H, m), 3.21-3.28 (1H, m), 8.24 (1H, d,J=2.3 Hz), 8.36 (1H, d, J=2.3 Hz).

-   The 6^(th) step: N,N-Dimethylformamide (40 ml) was added to compound    (126)(2.00 g) in a nitrogen stream, cooled in an ice bath with    stirring and sodium methoxide (2.074 g) was added therein. After    stirring at room temperature for 1.5 hours, the reaction solution    was warmed up to 60° C. and stirred for 2 hours. It was cooled in a    ice bath, neutralized by the addition of 2N hydrochloric acid and    extracted with ethyl acetate. The organic layer was washed with 2M    aqueous solution of potassium carbonate and brine and dried over    anhydrous sodium sulfate. The solvent was evaporated under reduced    pressure and the residue was purified with a silicagel column    chromatography to give compound (127)(1.69 g).

¹H-NMR (CDCl₁₋₃) δ: 1.52 (9H, s), 1.70 (3H, s), 1.96-2.03 (1H, m),2.54-2.61 (1H, m), 2.80-2.85 (1H, m), 2.97-3.00 (1H, m), 3.97 (3H, s),7.62 (1H, d, J=1.5 Hz), 8.15 (1H, d, J=1.5 Hz).

-   The 7^(th) step: Compound (127)(1.571 g),    trisdibenzylideneacetonedipalladium (0.414 g) and    butynyl-1-adamantylphosphine (0.324 g) were dissolved in toluene    under a nitrogen stream, and a solution of 1.6M lithium    hexamethyldisilazide/tetrahydrofuran (5.66 ml) was added at room    temperature with stirring. The reaction solution was warmed up to    80° C. and stirred for 3 hours. Then diethyl ether and 1N    hydrochloric acid were added with stirring under ice cooling. After    stirring for 5 minutes, it was neutralized by the addition of a    saturated aqueous solution of sodium carbonate, extracted with ethyl    acetate and dried over anhydrous sodium sulfate. The solvent was    evaporated under reduced pressure and the residue was purified with    a silicagel column chromatography to give compound (128)(1.55 g).

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 1.72 (3H, s), 1.86-1.93 (1H, m), 2.02(2H, s), 2.52-2.59 (1H, m), 2.74-2.79 (1H, m), 3.13-3.18 (1H, m), 3.90(3H, s), 6.96 (1H, d. J=2.3 Hz), 7.59 (1H, d, J=1.8 Hz).

-   The 8^(th) step: Compound (128)(0.20 g),    5-methylpyridine-2-carboxylic acid (0.10 g) and    O-(7-azabenzotriazole-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate (HATU)(0.28 g) were dissolved in    N,N-dimethylformamide (2 ml), triethylamine (0.119 ml) was added and    the mixture was stirred at room temperature for 1.0 hours. A 2M    aqueous solution of potassium carbonate was added, extracted with    ethyl acetate, and the organic layer was washed with brine and dried    over anhydrous sodium sulfate. The solvent was evaporated under    reduced pressure and the resulted residue was dissolved in    chloroform (4.0 ml), trifluoroacetic acid (1.0 ml) was added and the    mixture was stirred at room temperature for 3 hours. The solvent was    evaporated under reduced pressure, the residue was made basic by the    addition of a 2.0M aqueous solution of potassium carbonate,    extracted with ethyl acetate and the organic layer was washed with    water and dried over anhydrous magnesium sulfate. The solvent was    evaporated under reduced pressure and the residue was purified with    a silicagel column chromatography to give compound (680)(0.096 g).

1H-NMR (DMSO-d₆) δ: 1.47 (3H, s), 1.77-1.83 (1H, m), 2.34-2.39 (1H, m),2.48-2.53 (1H, m), 2.63 (3H, s), 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86(2H, br s), 8.10 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.5 Hz), 8.69 (1H,s), 9.14 (1H, s), 10.69 (11H, s).

-   The 9^(th) step: Compound (680)(0.096 g) and sodium iodide (0.193 g)    were dissolved in acetonitrile (5.0 ml), trimethylsilylchloride    (0.164 ml) was added and the mixture was stirred at room temperature    for 2.5 hours. Sodium iodide (0.193 g) and trimethyl silylchloride    (0.164 ml) were added and stirring was continued at room temperature    for 12 hours. A 2.0M aqueous solution of potassium carbonate,    extracted with ethyl acetate and the organic layer was washed with    water and dried over anhydrous magnesium sulfate. The solvent was    evaporated under reduced pressure to give compound (681)(0.073 g) as    a crude product.

¹H-NMR (DMSO-d₆) δ: 1.52 (3H, s), 1.80-1.85 (1H, m), 2.62 (3H, s),2.64-2.69 (2H, m), 2.96-3.01 (1H, m), 7.77 (1H, d, J=2.5 Hz), 7.96 (1H,d, J=2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).

-   The 10^(th) step: Compound (681)(0.031 g) was dissolved in    tetrahydrofuran (2.0 ml), di-tert-butyldicarbonate (0.030 ml) was    added and the mixture was stirred at room temperature for 1.5 hours.    Di-tert-butyldicarbonate (0.030 ml) was further added and the    stirring was continued at room temperature for 2.0 hours. The    reaction solution was concentrated under reduced pressure, the    resulted residue was dissolved in N, N-dimethylformamide (0.5 ml)    and potassium carbonate (23.9 mg) was added. A solution of methyl    iodide (12.2 mg) in N,N-dimethylformamide (0.5 ml) was added with    stirring at room temperature. After stirring at room temperature for    3 hours, methyl iodide (11.05 mg) was added and the mixture was    stirred at room temperature for 2 hours. Brine was added, extracted    with ethyl acetate and the organic layer was washed with water and    dried over anhydrous magnesium sulfate. The solvent was evaporated    under reduced pressure, the resulted residue was dissolved in    chloroform (2.0 ml), trifluoroacetic acid (0.5 ml) was added and the    mixture was stirred at room temperature for 3 hours. The reaction    solution was concentrated under reduced pressure, the resulted    residue was made alkaline by the addition of a 2.0M aqueous solution    of potassium carbonate, extracted with ethyl acetate and the organic    layer was washed with water and dried over anhydrous magnesium    sulfate. The solvent was evaporated under reduced pressure and the    residue was purified with a silicagel column chromatography to give    compound (682)(4.2 mg).

¹H-NMR (DMSO-d₆) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m),2.62 (3H, s), 2.64-2.69 (1H, m), 2.74 (3H, s), 2.92-2.98 (1H, m), 7.90(1H, d, J=2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57(1H, s).

The other compounds are prepared in the same manner. Chemical structuresand physical constants are shown below.

TABLE 1 Com- pound No. Structure 1

2

3

4

5

TABLE 2 Com- pound No. Structure 6

7

8

9

10

TABLE 3 Com- pound No. Structure 11

12

13

14

15

TABLE 4 Com- pound No. Structure 16

17

18

19

20

TABLE 5 Com- pound No. Structure 21

22

23

24

26

TABLE 6 Com- pound No. Structure 27

28

29

30

31

TABLE 7 Com- pound No. Structure 32

33

34

35

36

TABLE 8 Com- pound No. Structure 37

38

39

40

41

TABLE 9 Com- pound No. Structure 42

43

44

45

46

TABLE 10 Com- pound No. Structure 47

48

49

50

51

TABLE 11 Com- pound No. Structure 52

53

54

55

56

TABLE 12 Compound No. Structure 57

58

59

60

61

TABLE 13 Compound No. Structure 62

63

64

65

66

TABLE 14 Compound No. Structure 67

68

69

70

71

TABLE 15 Compound No. Structure 72

73

74

75

76

TABLE 16 Compound No. Structure 77

78

79

80

81

TABLE 17 Compound No. Structure 82

83

84

85

86

TABLE 18 Compound No. Structure 87

88

89

90

91

TABLE 19 Compound No. Structure 92

93

94

95

96

TABLE 20 Compound No. Structure 97

98

99

100

101

TABLE 21 Compound No. Structure 102

103

104

105

106

TABLE 22 Compound No. Structure 107

108

109

110

111

TABLE 23 Compound No. Structure 112

113

114

115

116

TABLE 24 Compound No. Structure 117

118

119

120

121

TABLE 25 Compound No. Structure 122

123

124

125

126

TABLE 26 Compound No. Structure 127

128

129

130

131

TABLE 27 Compound No. Structure 132

133

134

135

136

TABLE 28 Compound No. Structure 137

138

139

140

TABLE 29 Compound No. Structure 141

142

143

144

145

TABLE 30 Compound No. Structure 146

147

148

149

150

TABLE 31 Compound No. Structure 151

152

153

154

155

TABLE 32 Com- pound No. Structure 156

157

158

159

160

TABLE 33 Compound No. Structure 161

162

163

164

165

TABLE 34 Compound No. Structure 166

167

168

169

170

171

TABLE 35 Compound MS No. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 1 1H-NMR (CDCl3) δ: 6.69 (1.0H, br s), 8.57 (1.0H, s),8.53-8.41 (1.0H, m), 8.36-8.33 (1.0H, m), 7.90-7.81 (1.0H, m), 7.56(1.0H, br s), 7.41-7.29 (2.0H, m), 7.00-6.88 (2.0H, m), 2.88-2.63 (2.0H,m), 2.50-2.38 (1.0H, m), 2.06-2.00 (1.0H, m), 1.66 (3.0H, 2 344 3 1H-NMR(CDCl3) δ: 7.79 (1.0H, br 3), 7.65-7.64 (1.0H, m), 7.48-7.41 (1.0H, m),7.31 (1.0H, t, J = 8.01 Hz), 7.04-7.01 (1.0H, m), 6.23 (1.0H, br s),2.93-2.65 (2.0H, m), 2.57 (3.0H, br s), 2.40 (1.0H, ddd, J = 14.11,5.34, 343 Hz), 2.27 (3.0H, br s), 2.09-1.92 (1.0H, m), 1.67 (3.0H. s). 41H-NMR (CDCl3) δ: 7.86-7.83 (1.0H, m), 7.45-7.42 (1.0H, m), 7.35 (1.0H,t, J = 12.96 Hz), 7.21 (1.0H, br s), 7.04-7.01 (1.0H, m), 4.23 (3.0H,s), 2.90-2.86 (1.0H, m), 2.77-2.61 (1.0H, m), 2.38-2.30 (1.0H, m),1,99-1.89 (1.0H, m), 1.60 (3.0H, s). 5 1H-NMR (DMSO-d6) δ: 9.81 (1.0H,br s), 7.70-7.65 (2.0H, m), 7.22 (1.0H, t, J = 7.85 Hz), 7.06-7.03(1.0H, m), 6.53 (1.0H, s), 2.92-2.85 (1.0H, m), 2.61-2.52 (1.0H, m),2.28 (3.0H, s), 2.02-1.97 (1.0H, m), 1.73-1.67 (1.0H, m), 1.39 (3.0H,s). 6 425 7 415 8 361 9 331 10 347 11 360 12 379 13 367 14 331 15 1H-NMR(DMSO-d6) δ: 10.02 (1.0H, s), 7.81-7.55 (2.0H, m), 7.25 (1.0H, t, J =7.93 Hz), 7.09 (1.0H, d, J = 7.73 Hz), 6.26 (1.0H, s), 3.86 (3.0H, s),2.91-2.87 (1.0H, m), 2.59-2.54 (1.0H, m), 2.00-1.96 (1.0H, m), 1.75-1.62(1.0H, m), 1.39 (3.0H, s). 16 404 17 422 18 360 19 349 20 349 21 388 22365 23 392 24 385 26 1H-NMR (MeOD) δ: 1.73(1H, s), 1.98(1H, s), 2.29(1H,s), 2.76(1H, s), 6.58(1H, s), 6.79(1H, s), 6.92(1H, s), 7.13(1H, s),8.01(1H, s), 8.55(1H, S) 27 1H-NMR (DMSO-d6) δ: 1.65(1H, s), 2.07(1H, t,J = 13.1 Hz), 2.57(1H, d, J = 11.6 Hz), 3.10(1H, s), 7.10(1H, d, J = 7.1Hz), 7.42(1H, t, J = 7.5 Hz), 7.72(2H, s), 7.84(1H, d, J = 8.3 Hz),7.92(1H, t, J = 9.5 Hz), 8.55(1H, s), 10.74 (1H, s) 28 358 29 1H-NMR(CDCl3) δ: 1.71(s3H, s), 2.00(1H, d, J = 8.8 Hz), 2.45(1H, d, J = 12.4Hz), 2.78(1H, t, J = 12.5 Hz), 2.88(aH, s, J = 13.6 Hz), 3.94(3H, s),5.30(1H, s) 7.05(1H, d, J = 7.8 Hz), 7.35(1H, t, J = 8.2 Hz), 7.48(1H,s), 7.56(1H, s), 7.65(1H, d, J = 7.8 Hz), 9.58(1H, s)

TABLE 36 Compound MS NO. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 30 376 31 1H-NMR (MeOD) δ: 1.75(3H, s), 2.10-2.13(1H, m),2.49-2.62(1H, m), 2.65-2.71(2H, m), 2.80(3H, s), 7.02(1H, d, J = 8.6Hz), 7.41(1H, t, J = 7.8 Hz), 7.53(1H, s), 8.12(1H, d, J = 8.1 Hz),9.34(2H, s), 9.79(1H, s) 32 372 33 373 34 1H-NMR (DMSO-d6) δ: 1.63(3H,s), 1.70(3H, s, J = 5.3 Hz), 1.99-2.02(1H, br m), 2.28(1H, s),2.57-2.60(1H, dr m), 3.07(1H, d, J = 10.1 Hz), 4.65(2H, s), 5.70(1H, d,14.1 Hz), 5.91(1H, d, 7.3 Hz), 7.06(1H, s), 7.36(1H, s), 7.59(1H, d, J =5.1 Hz), 7.82 (1H, s), 7.89(1H, s, J 5.1 Hz), 8.36(1H, s), 10.48(1H, s)35 395 36 423 37 412 38 396 39 238 40 408 41 428 42 379 43 390 44 386 45420 46 435 47 1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.69-1.75 (1H, m),2.01-2.05 (1H, m), 2.55-2.58 (1H, m), 2.74-2.76 (2H, m), 2.88-2.91 (1H,m), 7.06 (1H, d, J = 7.8 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.70-7.73 (2H,m), 7.91 (1H, br s), 7.99 (1H, s), 8.63 (1H, s), 9.97 (1H, s). 48 1H-NMR(DMSO-d6) δ: 1.42 (3H, s), 1.71-1.85 (3H, m), 2.04-2.08 (1H, m),2.56-2.58 (1H, m), 2.82 (2H, t, J = 7.2 Hz), 2.88-2.93 (1H, m),3.41-3.43 (2H, m), 7.06 (1H, d, J = 7.8 Hz), 7.26 (1H, t, J = 7.6 Hz),7.70-7.73 (2H, m), 7.99 (2H, s), 8.65 (1H, s), 10.00 (1H, s). 49 1H-NMR(DMSO-d6) δ: 1.57 (3H, s), 1.62 (3H, s), 1.94-1.97 (1H, m), 2.37-2.40(1H, m), 2.56-2.60 (1H, m), 2.80-2.82 (2H, m), 3.03-3.06 (1H, m), 7.04(1H, d, J = 7.6 Hz), 7.34 (1H, t, J = 7.6 Hz), 7.78-7.82 (2H, m), 8.01(1H, s), 8.06 (1H, br s), 8.64 (1H, s), 10.13 (1H, s). 50 1H-NMR(DMSO-d6) δ: 1.45 (3H, s), 1.76-1.79 (1H, m), 2.09-2.13 (1H, m), 2.40(3H, br s), 2.57-2.60 (1H, m), 2.83 (2H, t, J = 5.9 Hz), 2.93-2.94 (1H,m), 3.49-3.51 (2H, m), 5.74 (1H, s), 7.06 (1H, d, J = 7.6 Hz), 7.27 (1H,t, J = 7.8 Hz), 7.74 (1H, br s), 7.77 (1H, s), 7.95 (2H, br s), 8.02(1H, s), 8.66 (1H, s), 10.02 (1H, s). 51 1H-NMR (DMSO-d6) δ: 1.40 (3H,s), 1.70-1.75 (1H, m), 1.85-1.90 (2H, m), 1.93-2.02 (2H, m), 2.14-2.21(1H, m), 2.53-2.60 (1H, m), 2.86-2.94 (1H, m), 3.82 (1H, q, J = 7.1 Hz),3.98 (1H, q, J = 7.2 Hz), 4.35-4.39 (1H, m), 7.06 (1H, d, J = 7.6 Hz),7.23 (1H, t, J = 7.8 Hz), 7.56-7.60 (2H, m), 9.57 (1H, s).

TABLE 37 Compound MS NO. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 52 1H-NMR (DMSO-d6) δ: 1.38 (3H, s), 1.61-1.81 (5H, m),1.95-2.08 (2H, m), 2.53-2.58 (1H, m), 2.88 (4H, t, J = 6.6 Hz),3.65-3.68 (1H, m), 5.67-5.85 (2H, m), 7.04 (1H, d, J = 7.8 Hz), 7.22(1H, t, J = 7.8 Hz), 7.48 (1H, s), 7.59 (1H, d, J = 7.8 Hz), 9.87 (1H,s). 53 1H-NMR (DMSO-d6) δ: 1.39 (3H, S), 1.62-1.80 (5H, m), 1.99-2.07(2H, m), 2.52-2.58 (1H, m), 2.87-2.91 (3H, m), 3.68 (2H, dd, J = 8.7,5.9 Hz), 7.04 (1H, d, J = 7.6 Hz), 7.23 (1H, t, J = 8.0 Hz), 7.47 (1H,s), 7.61 (1H, d, J = 7.8 Hz), 9.90 (1H, s). 54 1H-NMR (DMSO-d6) δ: 1.40(3H, s), 1.70-1.75 (1H, m), 1.95-2.05 (2H, m), 2.09-2.37 (2H, m),2.52-2.57 (1H, m), 2.87-2.94 (1H, m), 4.03 (1H, q, J = 7.1 Hz), 4.19(1H, dd, J = 8.6, 4.3 Hz), 7.06 (1H, d, J = 7.3 Hz), 7.25 (1H, t, J =8.0 Hz), 7.49 (1H, s), 7.56 (1H, d, J = 7.8 Hz), 7.86 (1H, s), 10.01(1H, s). 55 1H-NMR (DMSO-d6) δ: 1.40 (3H, s), 1.69-1.75 (1 H, m),1.97-2.03 (2H, m), 2.09-2.36 (4H, m), 2.52-2.57 (1H, m), 2.87-2.93 (1H,m), 4.17-4.20 (1H, m), 7.06 (1H, d, J = 7.8 Hz), 7.25 (1H, t, J = 8.0Hz), 7.54 (2H, t, J = 8.0 Hz), 7.87 (1H, s), 10.00 (1H, s). 56 1H-NMR(DMSO-d6) δ: 1.40 (3H, s), 1.71-1.76 (1H, m), 2.00-2.03 (1H, m),2.19-2.26 (1H, m), 2.46-2.58 (5H, m), 2.88-2.94 (1H, m), 5.03-5.06 (1H,m), 7.09 (1H, d, J = 7.1 Hz), 7.27 (1H, t, J = 8.1 Hz), 7.50 (1H, s),7.56 (1H, d, J = 8.1 Hz), 10.22 (1H, s). 57 1H-NMR (DMSO-d6) δ: 1.40(3H, s), 1.69-1.75 (1H, m), 2.00-2.04 (1H, m); 2.19-2.27 (1H, m),2.46-2.57 (6H, m), 2.87-2.94 (1H, m), 5.03-5.06 (1H, m), 7.09 (1H, d, J= 8.3 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.51 (1H, s), 7.56 (1H, d, J = 8.3Hz), 10.22 (1H, s). 58 1H-NMR (DMSO-d6) δ: 1.48 (3H, s), 1.78-1.84 (1H,m), 2.11-2.18 (1H, m), 2.55-2.61 (1H, m), 2.93-2.99 (1H, m), 7.14 (1H,d, J = 7.8 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.77-7.82 (2H, m), 8.93 (1H,s), 9.11 (1H, s). 59 1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.73-1.78 (1H,m), 2.01-2.08 (1H, m), 2.54-2.59 (1H, m), 2.89-2.96 (1H, m), 7.16 (1H,d, J = 8.1 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.57 (1H, s), 7.68 (1H, d, J =7.1 Hz), 8.70 (1H, d, J = 2.5 Hz), 8.77 (1H, d, J = 2.3 Hz), 10.80 (1H,s). 60 1H-NMR (DMSO-d6) δ: 1.42 (3H, s), 1.70-1.76 (1H, m), 2.01-2.06(1H, m), 2.54-2.60 (1H, m), 2.88-2.95 (1H, m), 3.97 (3H, s), 7.12 (1H,d, J = 7.8 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.62-7.68 (2H, m), 8.29 (1H,d, J = 2.3 Hz), 8.40 (1H, d, J = 2.5 Hz), 10.53 (1H, s). 61 1H-NMR(DMSO-d6) δ: 0.91 (3H, t, J = 7.2 Hz), 1.32-1.40 (5H, m), 1.51-1.58 (2H,m), 1.68-1.73 (1H, m), 1.97-2.05 (0H, m), 2.55-2.60 (1H, m), 2.85-2.92(1H, m), 5.77 (2H, br s), 7.07 (1H, d, J = 7.6 Hz), 7.25 (1H, t, J = 8.0Hz), 7.73 (2H, t, J = 6.7 Hz), 7.83-7.87 (1H, m), 7.96 (1H, s), 8.64(1H, s), 9.95 (1H, s). 62 1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.71-1.77(1H, m), 2.02-2.09 (1H, m), 2.55-2.61 (1H, m), 2.87-2.95 (1H, m), 3.31(3H, s), 3.70-3.74 (2H, m), 4.51-4.54 (2H, m), 7.11 (1H, d, J = 7.1 Hz),7.29 (1H, t, J = 7.7 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.80 (1H, s), 8.43(1H, s), 8.87 (1H, s), 10.35 (1H, s).

TABLE 38 Compound MS No. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 63 1H-NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7.5 Hz), 1,43 (3H, s),1.71-1.77 (1H, m), 2.01-2.09 (1H, m), 2.55-2.61 (1H, m), 2.90-2.96 (3H,m), 7.12 (1H, d, J = 7.8 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.76 (1H, d, J =8.1 Hz), 7.82 (1H, s), 8.70 (1H, s), 9.18 (1H, s), 10.53 (1H, s). 641H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.70-1.75 (1H, m), 1.99-2.06 (1H, m),2.52-2.57 (1H, m), 2.87-2.94 (1H, m), 7.11 (1H, d, J = 7.6 Hz), 7.28(1H, t, J = 7.8 Hz), 7.47-7.59 (5H, m), 7.65 (2H, d, J = 7.6 Hz), 8.30(0H, s). 65 1H-NMR (DMSO-d6) δ: 1.38 (3H, s), 1.67-1.72 (1H, m),1.94-2.00 (1H, m), 2.03 (3H, s), 2.50-2.55 (1H, m), 2.85-2.92 (1H, m),7.06 (1H, d, J = 7.1 Hz), 7.23 (1H, t, J = 7.7 Hz), 7.48 (2H, t, J = 8.3Hz), 10.55 (1H, s). 66 707.0(2M + 1) 67 743.1(2M + 1) 68 1H-NMR (DMSOd6) δ: 1.45 (3H, s), 1.74-1.80 (1H, m), 2.06-2.13 (1H, m), 2.56-2.61(1H, m), 2.90-2.97 (1H, m), 7.15 (1H, d, J = 7.6 Hz), 7.33 (1H, t, J =7.7 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.87 (1H, s), 8.04 (1H, s), 8.45 (1H,s), 9.29 (2H, d, J = 8.3 Hz), 10.79 (1H, s). 69 1H-NMR (DMSO-d6) δ: 1.43(3H, s), 1.71-1.76 (1H, m), 2.02-2.09 (1H, m), 2.55-2.63 (4H, m),2.88-2.94 (1H, m), 7.12 (1H, d, J = 8.1 Hz), 7.29 (1H, t, J = 7.8 Hz),7.74 (1H, d, J = 8.1 Hz), 7.81 (1H, s), 8.70 (1H, s), 9.08 (1H, s),10.45 (1H, s). 70 1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.71-1.77 (1H, m),2.02-2.09 (1H, m), 2.55-2.61 (1H, m), 2.87-2.95 (1H, m), 3.31 (3H, s),3.70-3.74 (2H, m), 4.51-4.54 (2H, m), 7.11 (1H, d, J = 7.1 Hz), 7.29(1H, t, J = 7.7 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.80 (1H, s), 8.43 (1H,S), 8.87 (1H, S), 10.35 (1H, s). 71 1H-NMR (DMSO-d6) δ: 0.94 (3H, t, J =7.3 Hz), 1.43-1.47 (4H, m), 1.72-1.79 (3H, m), 2.02-2.09 (1H, m), 2.58(1H, t, J = 9.7 Hz), 2.91 (1H, s), 4.40 (2H, t, J = 6.6 Hz), 7.11 (1H,d, J = 7.8 Hz), 7.29 (1H, t, J = 8.1 Hz), 7.75 (1H, d, J = 7.3 Hz), 7.80(1H, s), 8.37 (1H, s), 8.86 (1H, s), 10.34 (1H, s). 72 771.1(2M + 1) 731H-NMR (DMSO-d6) δ: 1.40 (3H, s), 1.68-1.73 (1H, m), 1.98-2.05 (1H, m),2.11 (3H, s), 2.55-2.60 (1H, m), 2.69 (2H, t, J = 6.8 Hz), 2.86-2.92(1H, m), 3.55-3.59 (2H, m), 5.77 (2H, br s), 7.07 (1H, d, J = 8.1 Hz),7.25 (1H, t, J = 8.0 Hz), 7.71-7.75 (2H, m), 8.00 (2H, s), 8.65 (1H, s),9.98 (1H, s). 74 1H-NMR (DMSO-d6) δ: 0.99 (3H, t, J = 7.5 Hz), 1,39 (3H,s), 1.56 (2H, td, J = 14.3, 7.2 Hz), 1.67-1.73 (1H, m), 1.95-2.02 (1H,m), 2.38 (2H, t, J = 6.8 Hz), 2.50-2.55 (1H, m), 2.86-2.93 (1H, m), 7.06(1H, d, J = 7.8 Hz), 7.23 (1H, t, J = 8.3 Hz), 7.47-7.51 (2H, m). 75839.1(2M + 1) 76 835.1(2M + 1) 77 782.9(2M + 1) 78 1H-NMR (DMSO-d6) δ:1.50 (3H, s), 1.79-1.84 (1H, m), 2.23-2.30 (1H, m), 2.55-2.60 (1H, m),2.96-3.02 (1H, m), 7.16 (1H, dd, J = 11.6, 8.8 Hz), 7.75-7.78 (2H, m),8.89 (1H, s), 9.07 (1H, s), 10.74 (1H, br s).

TABLE 39 Compound MS NO. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 79 1H-NMR (DMSO-d6) δ: 1.49 (4H, s), 1.77-1.83 (1H, m),2.16-2.23 (1H, m), 2.56-2.62 (1H, m), 2.95-3.01 (1H, m), 5.87 (2H, brs), 7.17 (1H, dd, J = 11.7, 8.5 Hz), 7.76-7.82 (2H, m), 9.96 (2H, d, J =3.8 Hz), 10.82 (1H, s). 80 1H-NMR (DMSO-d6) δ: 1.33 (3H, t, J = 7.2 Hz),1.42 (3H, s), 1.71-1.76 (1H, m), 2.03-2.07 (1H, m), 2.55-2.59 (1H, m),2.89-2.92 (1H, m), 3.25 (2H, q, J = 7.3 Hz), 7.11 (1H, d, J = 7.8 Hz),7.29 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.79 (1H, s), 8.66(1H, s), 9.07 (1H, s), 10.45 (1H, s). 81 831.1(2M + 1) 82 850.9(2M + 1)83 795.0(2M + 1) 84 758.8(2M + 1) 85 750.9(2M + 1) 86 795.1(2M + 1) 871H-NMR (DMSO-d6) δ: 1.01 (6H, d, J = 6.8 Hz), 1.44 (3H, s), 1.73-1.78(1H, m), 2.05-2.13 (2H, m), 2.56-2.61 (1H, m), 2.89-2.95 (1H, m), 4.19(2H, d, J = 6.6 Hz), 7.12 (1H, d, J = 8.1 Hz), 7.29 (1H, t, J = 7.8 Hz),7.76 (1H, d, J = 7.8 Hz), 7.82 (1H, s), 8.41 (1H, d, J = 1.3 Hz), 8.87(1H, s), 10.36 (1H, s). 88 1H-NMR (DMSO-d6) δ: 1.70 (3H, s), 2.02-2.08(1H, m), 2.58-2.64 (2H, m), 3.15-3.19 (1H, m), 5.16 (2H, q, J = 8.8 Hz),7.27 (1H, dd, J = 11.9, 8.8 Hz), 7.85-7.98 (2H, m), 8.62 (1H, s), 8.92(1H, s), 10.83 (1H, s). 89 1H-NMR (DMSO-d6) δ: 1.65 (3H, s), 2.04-2.11(1H, m), 2.54-2.62 (3H, m), 2.83-2.95 (2H, m), 3.11-3.14 (1H, m), 4.65(2H, t, J = 5.8 Hz), 7.09 (1H, d, J = 7.6 Hz), 7.42 (1H, t, J = 8.0 Hz),7.87-7.92 (2H, m), 8.43 (1H, s), 8.91 (1H, s), 10.63 (1H, s). 90 1H-NMR(DMSO-d6) d: 1.41 (3H, s), 1.69-1.74 (1H, m), 2.00-2.04 (1H, m),2.56-2.61 (1H, m), 2.87-2.92 (1H, m), 3.24 (6H, s), 3.37-3.52 (12H, m),3.59 (2H, t, J = 4.5 Hz), 3.80 (2H, t, J = 4.3 Hz), 4.52 (2H, t, J = 4.4Hz), 5.81 (2H, br s), 7.12 (1H, d, J = 7.6 Hz), 7.28 (1H, t, J = 8.0Hz), 7.75 (1H, d, J = 8.3 Hz), 7.81 (1H, s), 8.42 (1H, s), 8.87 (1H, s),10.33 (1H, s). 91 1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.69-1.75 (1H, m),1.85 (3H, s), 1.98-2.05 (1H, m), 2.55-2.61 (1H, m), 2.86-2.93 (1H, m),5.09 (2H, d, J = 2.0 Hz), 5.79 (2H, br s), 7.12 (1H, d, J = 7.8 Hz),7.28 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.3 Hz), 7.80 (1H, s), 8.45(1H, s), 8.90 (1H, s), 10.36 (1H, s). 92 1H-NMR (DMSO-d6) δ: 1.41 (4H,s), 1.69-1.74 (1H, m), 1.98-2.05 (1H, m), 2.56-2.61 (1H, m), 2.87-2.93(1H, m), 4.74 (2H, td, J = 15.0, 3.1 Hz), 5.79 (2H, br s), 6.34-6.61(1H, m), 7.12 (1H, d, J = 7.8 Hz), 7.29 (1H, t, J = 8.0 Hz), 7.74 (1H,d, J = 8.1 Hz), 7.81 (1H, s), 8.54 (1H, s), 8.90 (1H, s), 10.40 (1H, s).93 837.0(2M + 1) 94 1H-NMR (DMSO-d6) δ: 1.41 (4H, s), 1.69-1.74 (1H, m),1.98-2.05 (1H, m), 2.55-2.61 (2H, m), 2.71-2.75 (1H, m), 2.67-2.93 (1H,m), 4.49-4.61 (4H, m), 5.05-5.11 (1H, m), 5.79 (2H, br s), 7.12 (1H, d,J = 7.3 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.81(1H, s), 8.47 (1H, s), 8.88 (1H, S), 10.36 (1H, s). 95 801.0(2M + 1)

TABLE 40 Compound MS No. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 96 1H-NMR (DMSO-d6) δ: 1.42 (3H, s), 1.70-1.78 (1H, m),1,97-2.04 (3H, m), 2.55-2.60 (1H, m), 2.87-2.93 (1H, m), 3.26 (3H, s),3.49 (2H, t, J = 6.2 Hz), 4.20 (2H, t, J = 6.4 Hz), 5.86 (2H, br s),7.10 (1H, d, J = 7.8 Hz), 7.28 (1H, t, J = 8.1 Hz), 7.61 (1H, dd, J =8.8, 2.8 Hz), 7.77-7.78 (2H, m), 8.11 (1H, d, J = 8.6 Hz), 8.38 (1H, d,J = 2.8 Hz), 10.32 (1H, s). 97 1H-NMR (DMSO-d6) δ: 1.41 (3H, s),1.70-1.75 (1H, m), 1.99-2.06 (1H, m), 2.56-2.61 (1H, m), 2.87-2.93 (1H,m), 4.40-4.50 (2H, m), 4.74-4.88 (2H, m), 5.81 (2H, br s), 7.10 (1H, d,J = 7.6 Hz), 7.28 (1H, t, J = 8.2 Hz), 7.66 (1H, dd, J = 8.8, 2.8 Hz),7.77-7.78 (2H, m), 8.13 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.5 Hz),10.33 (1H, s). 98 1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.74-1.76 (7H, m),1.99-2.06 (1H, m), 2.56-2.61 (1H, m), 2.86-2.93 (1H, m), 4.71 (2H, d, J= 6.3 Hz), 5.44-5.49 (1H, m), 5.81 (2H, br s), 7.10 (1H, d, J = 7.3 Hz),7.28 (1H, t, J = 8.1 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.77 (2H, s), 8.11(1H, d, J = 8.6 Hz), 8.36 (1H, s), 10.30 (1H, s). 99 799.0(2M + 1) 100827.0(2M + 1) 101 867.1(2M + 1) 102 865.1(2M + 1) 103 382 104 412 1051H-NMR (DMSO-d6) δ: 1.41 (4H, s), 1.69-1.74 (1H, m), 1.98-2.05 (1H, m),2.55-2.60 (1H, m), 2.69-2.75 (2H, m), 2.86-2.93 (2H, m), 4.49 (2H, t, J= 6.4 Hz), 5.82 (2H, br s), 7.12 (1H, d, J = 7.3 Hz), 7.28 (1H, t, J =7.7 Hz), 7.74 (1H, d, J = 7.8 Hz), 7.80 (1H, s), 8.42 (1H, s), 8.88 (1H,s), 10.34 (1H, s). 106 1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.69-1.76 (3H,m), 1.98-2.05 (1H, m), 2.56-2.61 (1H, m), 2.64-2.69 (2H, m), 2.87-2.93(1H, m), 4.45 (2H, t, J = 6.4 Hz), 5.80 (2H, br s), 7.12 (1H, d, J = 7.8Hz), 7.28 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.3 Hz), 7.80 (1H, s),8.42 (1H, s), 8.88 (1H, s), 10.34 (1H, s). 107 1H-NMR (DMSO-d6) δ:1.47-1.54 (1H, m), 1.86 (3H, s), 2.03-2.09 (1H, m), 2.88-2.94 (1H, m),3.09-3.15 (1H, m), 4.43-4.47 (1H, m), 5.08-5.11 (2H, m), 5.76 (2H, brs), 7.04-7.06 (1H, m), 7.27-7.31 (1H, m), 7.68-7.70 (1H, m), 7.79 (1H,s), 8.45 (1H, s), 8.89 (1H, s), 10.39 (1H, s). 108 412 109 398 1101H-NMR (DMSO-d6) δ: 1.45 (3H, s), 1.75-1.81 (1H, m), 2.08-2.14 (1H, m),2.56-2.61 (1H, m), 2.90-2.97 (1H, m), 7.08 (1H, d, J = 6.8 Hz),7.27-7.36 (2H, m), 7.77-7.79 (2H, m), 8.01 (1H, d, J = 8.6 Hz), 8.22(1H, d, J = 2.8 Hz), 10.27 (1H, s). 111 1H-NMR (DMSO-d6) δ: 1.43 (3H,s), 1.75-1.80 (1H, m), 2.07-2.14 (1H, m), 2.56-2.61 (1H, m), 2.90-2.97(1H, m), 5.28 (2H, s) 7.09 (1H, d, J = 7.8 Hz), 7.23-7.32 (3H, m), 7.57(2H, dd, J = 8.3, 5.6 Hz), 7.70 (1H, dd, J = 8.7, 2.7 Hz), 7.78-7.81(2H, m), 8.13 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.8 Hz), 10.36 (1H,s). 112 441

TABLE 41 Compound MS No. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 113 1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.71-1.77 (1H, m),2.05-2.13 (7H, m), 2.56-2.61 (1H, m), 2.88-2.94 (1H, m), 5.75 (2H, s),7.12 (1H, d, J = 8.1 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.74-7.80 (2H, m),8.66 (1H, s), 8.93 (1H, s), 10.44 (1H, s). 114 1H-NMR (DMSO-d6) δ: 1.47(3H, s), 1.77-1.82 (1H, m), 2.13-2.20 (1H, m), 2.57-2.62 (1H, m),2.93-3.00 (1H, m), 3.75-3.79 (2H, m), 4.18 (2H, t, J = 4.4 Hz), 5.00(1H, br s), 5.89 (2H, br s), 7.12 (1H, dd, J = 11.4, 8.8 Hz), 7.58-7.63(1H, m), 7.72-7.82 (2H, m), 8.09 (1H, d, J = 8.6 Hz), 8.39 (1H, s),10.34 (1H, s). 115 416 116 1H-NMR (DMSO-d6) δ: 1.47 (4H, s), 1.76-1.81(1H, m), 2.15-2.22 (1H, m), 2.55-2.60 (1H, m), 2.93-2.99 (1H, m), 4.47(3H, s), 5.87 (2H, br s), 7.13 (1H, dd, J = 12.0, 8.7 Hz), 7.79 (2H,ddd, J = 18.3, 8.0, 3.1 Hz), 8.69 (1H, s), 9.23 (1H, s), 10.72 (1H, s).117 1H-NMR (DMSO-d6) δ: 1.48 (3H, s), 1.77-1.82 (1H, m), 2.14-2.21 (1H,m), 2.57-2.62 (1H, m), 2.93-3.00 (1H, m), 3.32 (3H, s), 4.56-4.59 (2H,m), 5.87 (2H, br s), 6.27-6.33 (1H, m), 6.75 (1H, d, J = 12.4 Hz), 7.13(1H, dd, J = 11.9, 8.8 Hz), 7.77-7.83 (2H, m), 8.77 (1H, s), 9.25 (1H,s), 10.64 (1H, s). 118 418 119 361 120 825.1(2M + 1) 121 416 122 1H-NMR(DMSO-d6) δ: 1.41 (3H, s), 1.68-1.74 (1H, m), 1.98-2.05 (1H, m), 2.21(6H, s), 2.55-2.60 (1H, m), 2.67 (2H, t, J = 5.6 Hz), 2.86-2.93 (1H, m),4.48 (2H, t, J = 5.4 Hz), 5.79 (2H, br s), 7.11 (1H, d, J = 7.8 Hz),7.28 (1H, t, J = 7.8 Hz), 7.73 (1H, d, J = 7.6 Hz), 7.79 (1H, s), 8.39(1H, s), 8.66 (1H, s), 10.33 (1H, s). 123 395 124 414 125 417 126 1H-NMR(DMSO-d6) δ: 1.45 (3H, s), 1.75-1.81 (1H, m), 2.13-2.20 (1H, m),2.55-2.60 (1H, m), 2.92-2.99 (1H, m), 3.88 (6H, s), 5.81 (2H, br s),7.08 (1H, dd, J = 11.6, 8.8 Hz), 7.50-7.55 (1H, m), 7.66-7.69 (1H, m),10.07 (1H, s). 127 380 128 372 129 418 130 412 131 1H-NMR (DMSO-d6) δ:1.48 (3H, s), 1.77-1.82 (1H, m), 2.18-2.25 (1H, m), 2.55-2.60 (1H, m),2.94-3.01 (1H, m), 4.72 (2H, t, J = 13.8 Hz), 6.45 (1H, t, J = 53.9 Hz),7.10-7.15 (1H, m), 7.74-7.79 (2H, m), 8.50 (1H, s), 8.87 (1H, s), 10.47(1H, s). 132 1H-NMR (DMSO-d6) δ: 1.49 (3H, s), 1.78-1.83 (1H, m),2.19-2.26 (1H, m), 2.56-2.60 (1H, m), 2.94-3.01 (1H, m), 4.61-4.86 (4H,m), 7.09-7.14 (1H, m), 7.75-7.79 (2H, m), 8.43 (1H, s), 8.84 (1H, s),10.43 (1H, s). 133 400

TABLE 42 Compound MS No. (M + 1) MP NMR (solvent, shift value: ascendingorder) uv 134 1H-NMR (DMSO-d6) δ: 1.37 (3H, t, J = 7.1 Hz), 1.49 (3H,s), 1.78-1.83 (1H, m), 2.19-2.26 (1H, m), 2.56-2.61 (1H, m), 2.95-3.01(1H, m), 4.44 (2H, q, J = 7.0 Hz), 7.13 (1H, dd, J = 11.6, 9.1 Hz),7.73-7.78 (2H, m), 8.35 (1H, s), 8.83 (1H, s), 10.41 (1H, s). 135 411136 412 137 1H-NMR (CDCl3) δ: 1.63 (3H, s), 1.81-1.91 (1H, m), 2.21-2.32(1H, m), 2.56-2.67 (1H, m), 2.75-2.83 (1H, m), 3.77 (3H, s), 5.24 (2H,s), 6.47 (1H, dd, J = 3.2, 0.6 Hz), 6.83 (2H, d, J = 8.9 Hz), 7.02 (1H,dd, 8.0, 1.8 Hz), 7.07 (1H, d, 3.2 Hz), 7.12 (2H, d, J = 8.9 Hz), 7.26(1H, dd, 1.8, 0.6 Hz), 7.57 (1H, d, J = 8.0 Hz). 138 400 139 246 140 356141 376 142 410 143 378 144 398 145 432 146 529 147 377 148 438 149 390150 212.2 151 211.0, 266.3, 301.8 152 285.2 153 403 154 403 155 404 156388 157 389 158 412 159 380 160 381 161 1H-NMR (DMSO-d6) δ: 1.47 (3H,s), 1.77-1.82 (1H, m), 2.15-2.21 (8H, m), 2.56-2.67 (3H, m), 2.93-3.00(1H, m), 4.21 (2H, t, J = 5.4 Hz), 5.88 (2H, br s), 7.11 (1H, dd, J =11.6, 9.3 Hz), 7.59-7.61 (1H, m), 7.73-7.80 (2H, m), 8.09 (1H, d, J =8.6 Hz), 8.37 (1H, s), 10.33 (1H, s). 162 402 163 408 164 464 165 459166 404 167 420 168 375 169 432 170 380 171 376

TABLE 43 Compound No. Structure MS(M + 1) 172

173

459 174

403 175

426 176

393

TABLE 44 Compound No. Structure MS(M + 1) 177

359 178

402 179

447 180

435 181

396

TABLE 45 Compound No. Structure MS(M + 1) 182

376 183

385 184

375 185

378 186

412

TABLE 46 Compound No. Structure MS(M + 1) 187

366 188

429 189

364 190

404 191

439

TABLE 47 Compound No. Structure MS(M + 1) 192

412 193

426 194

393 195

352 196

414

TABLE 48 Compound No. Structure MS(M + 1) 197

198

414 199

364 200

397 201

428

TABLE 49 Compound No. Structure MS (M + 1) 202

203

398 204

410 205

422 206

395

TABLE 50 Compound No. Structure MS (M + 1) 207

414 208

410 209

402 210

211

TABLE 51 Compound No. Structure MS (M + 1) 212

433 213

466 214

464 215

427 216

400

TABLE 52 Compound No. Structure MS (M + 1) 217

442 218

386 219

402 220

362 221

TABLE 53 Compound No. Structure MS (M + 1) 222

399 223

224

352 225

402 226

395

TABLE 54 Compound No. Structure MS (M + 1) 227

362 228

375 229

380 230

231

400

TABLE 55 Compound No. Structure MS (M + 1) 232

233

234

422 235

395 236

364

TABLE 56 Compound No. Structure MS (M + 1) 237

362 238

427 239

455 240

420 241

406

TABLE 57 Compound No. Structure MS (M + 1) 242

471 243

406 244

420 245

383 246

TABLE 58 Compound No. Structure MS (M + 1) 247

455 248

435 249

416 250

416

TABLE 59 Compound No. Structure MS (M + 1) 251

402 252

388 253

420 254

255

524

TABLE 60 Compound No. Structure MS (M + 1) 256

348 257

258

395 259

395 260

402

TABLE 61 Compound No. Structure MS (M + 1) 261

336 262

263

264

334 265

384

TABLE 62 Compound No. Structure MS (M + 1) 266

402 267

402 268

269

396 270

427

TABLE 63 Compound No. Structure MS (M + 1) 271

444 272

416 273

429 274

275

376

TABLE 64 Compound No. Structure MS(M + 1) 276

425 277

425 278

429 279

430 280

TABLE 65 Compound No. Structure MS(M + 1) 281

448 282

411 283

284

438 285

TABLE 66 Compound No. Structure MS(M + 1) 286

437 287

437 288

348 289

429 290

448

TABLE 67 Compound No. Structure MS(M + 1) 291

398 292

293

419 294

295

422

TABLE 68 Compound No. Structure MS(M + 1) 296

430 297

410 298

410 299

300

401

TABLE 69 Compound No. Structure MS(M + 1) 301

302

400 303

349 304

426 305

363

TABLE 70 Compound No. Structure MS(M + 1) 306

415 307

308

424 309

406 310

383

TABLE 71 Compound No. Structure MS(M + 1) 311

470 312

422 313

476 314

401 315

428

TABLE 72 Compound No. Structure MS(M + 1) 316

413 317

442 318

442 319

411 320

434

TABLE 73 Compound No. Structure MS(M + 1) 321

322

463 323

324

325

410

TABLE 74 Compound No. Structure MS(M + 1) 326

390 327

410 328

410 329

410 330

384

TABLE 75 Compound No. Structure MS(M + 1) 331

479 332

429 333

427 334

427 335

410

TABLE 76 Compound No. Structure MS(M + 1) 336

428 337

426 338

401 339

400 340

TABLE 77 Compound No. Structure MS(M + 1) 341

441 342

442 343

442 344

430 345

428

TABLE 78 Compound No. Structure MS(M + 1) 346

430 347

411 348

413 349

478 350

TABLE 79 Compound MS No. Structure (M + 1) 351

384 352

443 353

403 354

355

421

TABLE 8 Compound MS No. Structure (M + 1) 356

422 357

421 358

369 359

430 360

424

TABLE 81 Compound MS No. Structure (M + 1) 361

416 362

429 363

364

365

398

TABLE 82 Compound MS No. Structure (M + 1) 366

425 367

425 368

369

424

TABLE 83 Compound MS No. Structure (M + 1) 370

413 371

430 372

408 373

426 374

437

TABLE 84 Compound MS No. Structure (M + 1) 375

424 376

377

427 378

424

TABLE 85 Compound MS No. Structure (M + 1) 379

424 380

493 381

458 382

395 383

407

TABLE 86 Compound MS No. Structure (M + 1) 384

416 385

364 386

387

388

TABLE 87 Compound MS No. Structure (M + 1) 389

390

391

392

413 393

446

TABLE 88 Compound MS No. Structure (M + 1) 394

445 395

428 396

413 397

494 398

428

TABLE 89 Compound MS No. Structure (M + 1) 399

404 400

375 401

444 402

444 403

448

TABLE 90 Compound MS No. Structure (M + 1) 404

440 405

365 406

414 407

443 408

385

TABLE 91 Compound MS No. Structure (M + 1) 409

423 410

410 411

412

393 413

348

TABLE 92 Compound MS No. Structure (M + 1) 414

414 415

438 416

410 417

418

464

TABLE 93 Compound MS No. Structure (M + 1) 419

461 420

462 421

412 422

466 423

437

TABLE 94 Compound No. Structure MS(M + 1) 424

411 425

411 426

351 427

478 428

462

TABLE 95 Compound No. Structure MS(M + 1) 429

430

443 431

470 432

433

378

TABLE 96 Compound No. Structure MS(M + 1) 434

451 435

355 436

351 437

509 438

420

TABLE 97 Compound No. Structure MS(M + 1) 439

429 440

406 441

494 442

458 443

483

TABLE 98 Compound No. Structure MS(M + 1) 444

457 445

452 446

550 447

437

TABLE 99 Compound No. Structure MS(M + 1) 448

495 449

455 450

481 451

426

TABLE 100 Compound No. Structure MS(M + 1) 452

454 453

480 454

404 455

441

TABLE 101 Compound No. Structure MS(M + 1) 456

417 457

395 458

362 459

393 460

TABLE 102 Com- pound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 461

346 462

349 1H-NMR (DMSO-d6) d: 10.02 (1.0H, s), 8.59 (1.0H, s), 7.73-7.66(2.0H, m), 7.09 (1.0H, dd, J= 12.00, 8.97 Hz), 5.83 (2.0H, br s),2.97-2.95 (1.0H, m), 2.59-2.56 (1.0H, m), 2.17-2.16 (1.0H, m), 1.79-1.76(1.0H, m), 1.47 (3.0H, s). 483

362 464

441 465

456 466

1H-NMR (DMSO-d6) d: 10.70 (1.0H, s), 8.76 (1.0H, s), 8.36 (1.0H, s),8.03 (1.0H, s), 6.44 (1.0H, s), 5.93 (2.0H, br s), 3.00- 2.97 (1.0H, m),2.63-2.61 (1.0H, m), 2.19 (3.0H, s), 2.00-1.98 (1.0H, m), 1.82-1.80(1.0H, m), 1.60 (9.0H, s), 1.43 (3.0H, s).

TABLE 103 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 467

369 468

396 469

450 470

383 471

417 472

364

TABLE 104 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 473

361 474

332 475

378 476

345 477

392 478

365 479

359

TABLE 105 Compound MS NMR (solvent, No Structure (M + 1) MP shiftvalue:ascending order) uv 480

360 481

366 482

345 483

394 484

385 485

347 486

347

TABLE 106 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 487

347 488

362 489

405 490

381 491

379 492

421 493

379

TABLE 107 Compound MS NMR (solvent, No Structure (M + 1) MP shiftvalue:ascending order) uv 494

426 495

363 496

378 497

426 498

374 499

374 500

363

TABLE 108 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 501

400 502

384 503

359 504

367 505

365 506

365 507

365

TABLE 109 Compound MS MR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 508

365 509

411 510

363 511

363 512

393 513

408 514

413

TABLE 110 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 515

411 516

413 517

441 518

348 519

429 520

394 521

402

TABLE 111 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 522

378 523

441 524

380 525

379 526

414 527

428

TABLE 112 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 528

433 529

362 530

392 531

426 532

364 533

364

TABLE 113 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 534

404 535

394 536

383 537

428 538

404 539

401

TABLE 114 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 540

384 541

442 542

401 543

404 544

511 545

400

TABLE 115 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 546

1H-NMR (DMSO-d6) d: 10.92 (1H, s), 10.45 (1H, s), 8.45 (1H, s), 8.42(1H, s), 8.30 (1H, d, J=8.8 Hz), 7.79-7.78 (3H, m), 7.31 (1H, dd, J=12.3, 9.2 Hz). 3.22 (1H, d, J= 13.4 Hz), 2.72-2.65 (2H, m), 2.11 (1H, t,J=11.5 Hz), 1.73 (3H, s). 547

359 548

359 549

403 550

343 551

343

TABLE 116 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 552

363 553

348 554

363 555

374 556

383 557

1H-NMR (DMSO-d6) δ: 10.72 (1H. s), 8.93 (1H, s), 8.90 (1H, s), 8.49 (1H,s). 8.36 (1H, s). 8.24 (1H, s), 4.88-4.64 (4H, m), 3.03-2.97 (1H, m),2.65-2.58 (1H, m), 2.13-2.07 (1H, m), 1.89-1.81 (1H, m), 1.48 (3H, s).558

402

TABLE 117 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 559

418 560

387 561

411 562

431 563

342 564

372 565

390

TABLE 118 Com- pound MS NMR (solvent, No Structure (M + 1) MP shiftvalue:ascending order) uv 566

428 567

429 568

419 569

442 570

456 571

443 572

396

TABLE 119 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 573

447 574

430 575

458 576

412 577

426 578

426 579

440

TABLE 120 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 580

480 581

363 582

393 583

437 584

366 585

360 586

380

TABLE 121 Compound MS NMR (solvent, No Structure (M + 1) MP shiftvalue:ascending order) uv 587

363 588

323 589

250.9, 288.7 590

298.2 591

252.1, 305.3 592

250.9, 288.7 593

216.9, 292.3

TABLE 122 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 594

214.5, 289.9 595

297 596

250.9, 302.9 597

289.9 598

297 599

214.5, 289.9 600

404, 807 (2M + 1)

TABLE 123 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 601

448, 895 (2M + 1) 602

389 603

391 604

391 605

436 606

388

TABLE 124 Compound MS NMR (solvent,) No Structure (M + 1) MP shiftvalue:ascending order) uv 607

608

609

377 610

611

612

332

TABLE 125 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 613

346 614

615

616

617

618

TABLE 126 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 619

620

621

622

623

624

TABLE 127 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 625

626

627

628

629

630

TABLE 128 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 631

632

633

634

635

636

TABLE 129 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 637

387 638

639

640

641

642

TABLE 130 Compound MS NMR (solvent, No. Structure (M + 1) MP shiftvalue:ascending order) uv 643

644

475 645

397 646

414

TABLE 131 Compound MS No Structure (M + 1) NMR (solvent, shift value)647

404 648

377 649

388 650

389 651

453 652

399 653

371

TABLE 131 Compound MS No. Structure [M + 1] NMR (solvent, shift value)654

360 655

374 856

458 657

411 658

419 659

383 660

1H-NMR (CDCl3) δ: 1.84 (3H, d-like), 3.16 (1H, ddd, J=6.9, 12.6, 14.4Hz), 3.36 (1H, ddd, J=6.0, 12.6, 18.9 Hz), 4.61 (2H, br), 7.07 (1H, dd,J=8.7, 11.7 Hz), 7.49-7.63 (2H, m), 7.67 (1H, dd, J=3.0, 8.9 Hz), 7.95(1H, ddd, J=3.0, 6.9, 8.7 Hz), 8.41 (1H, m), 9.85 (1H, brs).

TABLE 133 Compound MS No. Structure [M + 1] NMR (solvent, shift value)661

1H-NMR (CDCl3) δ: 0.89 (3H,s), 1.11 (3H, d, J= 3.0 Hz), 1.67 (3H, d,J=4.2 Hz), 2.63 (1H, d, J= 12.0 Hz), 3.12 (1H, d, J=12.0 Hz), 4.29 (2H,br), 7.02 (1H, dd, J=8.7, 12.3 Hz), 7.49-7.64 (3H, m), 7.96 (1H, ddd,J=3.0, 6.6, 8.7 Hz), 8.45 (1 H, m), 9.81 (1H, brs). 662

1H-NMR (CDCl3) δ: 1.85 (3H, d-like), 2.69 (3H, s), 3.17 (1H, ddd, J=6.9,12.6. 14.4 Hz), 3.37 (1H, ddd, J=6.3, 12.9, 18.9 Hz), 4.54 (2H, brs),7.08 (1H, dd, J=8.7, 11.7 Hz). 7.69 (1H, dd, J=2.7, 6.9 Hz), 7.87 (1H,dd, J=2.4, 8.4 Hz), 7.93 (1H, ddd, J= 2.7, 6.6, 8.7 Hz), 8.24 (1H, dd,J=0.6, 8.4 Hz), 8.55 (1H, dd, J=0.6, 2.4 Hz), 9.82 (1H, brs). 663

1H-NMR (CDCl3) δ: 1.85 (3H, d-like), 3.18 (1H, ddd, J=7.2, 12.9. 15.0Hz). 3.37 (1H, ddd, J=6.0, 12.6, 18.9 Hz), 4.60 (2H, br), 7.08 (1H, dd,J=8.7, 11.7 Hz), 7.71 (1H, dd, J=3.0, 6.6 Hz), 7.90 (1H, ddd, J= 3.0,6.6, 8.7 Hz), 8.41 (1H, d, J=0.9 Hz), 9.35 (1H, d, J=0.9 Hz), 9.63 (1H,brs). 664

1H-NMR (CDCl3) δ: 1.83 (3H, d-like), 2.51 (3H, s), 3.16 (1H, ddd, J=6.9,12.9, 15.3 Hz), 3.34 (1H, ddd, J=6.3, 12.9, 19.2 Hz), 4.53 (2H, brs),7.05 (1H, dd, J=8.7, 11.4 Hz), 7.62 (1H, dd, J=2.7, 6.9 Hz), 7.82 (1H,ddd, J=2.7, 6.9, 8.7 Hz), 8.16 (1H, s), 8.70 (1H, brs). 665

1H-NMR (CDCl3) δ: 0.95 (3H, t, J=7.5 Hz), 1.32- 1.44 (2H, m), 1.59-1.69(2H, m), 1.85 (3H, d-like), 2.70 (2H, t, J=7.5 Hz), 3.17 (1H, ddd,J=6.9, 12.9, 15.3 Hz), 3.34 (1H, ddd, J=6.3, 12.9, 19.2 Hz), 4.53 (2H,brs), 7.07 (1H, dd, J=8.7, 11.7 Hz), 7.67- 7.70 (2H, m), 7.94 (1H, ddd,J=2.7, 6.6, 8.7 Hz), 8.18 (1H, dd, J=0.6, 7.8 Hz), 8.40 (1H, dd, J=0.6,1.8 Hz), 9.97 (1H, brs). 666

396 667

365

TABLE 134 Compound MS No. Structure [M + 1] NMR (solvent, shift value)668

366 669

403 670

1H-NMR (CDCl3) δ: 1.38 (3H, t, J=7.6 Hz), 1.63 (3H, s), 1.88-1.97 (1H,m), 2.41-2.50 (1H, m), 2.69- 2.78 (1H, m), 2.84 (2H, q, J=7.6 Hz),2.93-3.01 (1H, m), 7.02 (1H, dd, J=11.8, 8.8 Hz), 7.34 (1H, dd, J=7.1,2.8 Hz), 7.89 (1H, ddd, J=8.8, 4.3, 2.8 Hz), 8.16 (1H, s), 8.69 (1H, s).671

370 672

432 673

412 674

1H-NMR (CDCl₃) δ: 0.53-0.59 (1H, m), 0.65-0.72 (1H, m), 0.85-0.91 (1H,m), 1.14-1.17 (1H, m), 1.47 (3H, d, J=2.0 Hz). 2.46 (1H, d, J=12.1 Hz),2.69 (3H, s), 2.89 (1H, dd, J=12.1, 1.3 Hz), 7.06 (1H, dd, J=11.5, 8.8Hz), 7.45 (1H, dd, J=6.8, 2.8 Hz), 7.94 (1H, ddd, J=8.8, 4.0, 2.8 Hz),8.44 (1H, d, J= 1.3 Hz), 9.36 (1H, d, J=1.3 Hz), 9.60 (1H, s).

TABLE 135 Compound MS No. Structure [M + 1] NMR (solvent, shift value)675

402 676

426 677

396 678

430 679

372 680

¹H-HNMR (DMSO-d₆) δ: 1.47 (3H, s), 1.77-1.83 (1H, m), 2.34-2.39 (1H, m),2.48-2.53 (1H, m), 2.63 (3H, s) 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86(2H, br s), 8.10 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.5 Hz), 8.69 (1H,s), 9.14 (1H, s), 10.69 (1H, s). 681

¹H-NMR (DMSO-d₆) δ: 1.52 (3H, s), 1.80-1.85 (1H, m), 2.62 (3H, s),2.64-2.69 (2H, m), 2.96-3.01 (1H, m), 7.77 (1H, d, J=2.5 Hz), 7.96 (1H,d, J=2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).

TABLE 136 Compound MS No. Structure [M + 1] NMR (solvent, shift value)682

¹H-NMR (DMSO-d₆) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m),2.62 (3H, s), 2.64-2.69 (1H, m), 2.74 (3H, s), 2.92-2.98 (1H, m), 7.90(1H, d, J= 2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57(1H, s). 683

482 684

482 685

400 686

424 687

427 688

402

TABLE 137 Compound MS No. Structure [M + 1] NMR (solvent, shift value)689

390 690

413 691

374 692

428 693

1H-NMR (DMSO-d6) δ: 0.77 (3H, s), 1.30 (3H, s), 1.43 (3H, s), 1.71 (1H,d, J=13.8 Hz), 2.33 (1H, d, J= 13.8 Hz), 3.65 (1H, t, J=2.4 Hz), 5.13(2H, d, J= 2.4 Hz), 6.05 (2H, br), 7.19 (1H, d-like), 7.25 (1H, t, J=7.8 Hz). 7.71 (1H, d-like), 7.87 (1H, s-like), 8.47 (1H, d, J=1.2 Hz),8.90 (1H, d, J=1.2 Hz), 10.37 (1H, brs). 694

1H-NMR (DMSO-d6) δ: 0.77 (3H, s), 1.28 (3H, s), 1.42 (3H, s), 1.67 (1H,d, J=14.1 Hz), 2.23 (1H, d, J= 14.1 Hz), 4.02 (3H, s), 5.82 (2H, brs),7.19 (1H, d- like), 7.24 (1H, t, J=7.8 Hz), 7.70 (1H, d-like), 7.86 (1H,s-like), 8.40 (1H, d, J=1.2 Hz), 8.89 (1H, d, J= 1.2 Hz), 10.31 (1H,brs). 695

1H-NMR (DMSO-d6) δ: 0.79 (3H, s), 1.32 (3H, s), 1.46 (3H, s), 1.78 (1H,d, J=14.1 Hz), 1.86 (3H, t, J= 2.4 Hz), 2.39 (1H, d, J=14.1 Hz), 5.90(1H, q, J= 2.4 Hz), 5.49 (2H, br), 7.18 (1H, d-like), 7.27 (1H, t, J=7.8 Hz), 7.73 (1H, d-like), 7.87 (1H, s-like), 8.44 (1 H, d, J=1.2 Hz),8.89 (1H, d, J=1.2 Hz), 10.38 (1H, brs).

TABLE 138 Compound MS No. Structure [M + 1] NMR (solvent, shift value)696

1H-NMR (DMSO-d6) δ: 0.77 (3H, s), 1.30 (3H, s), 1.43 (3H, s), 1.71 (1H,d, J=14.1 Hz) 2.32 (1H, d, J= 14.1 Hz), 5.95 (2H, br), 7.22 (1H,d-like), 7.27 (1H, t, J=7.8 Hz), 7.75 (1H, d-like), 7.88 (1H, s-like),8.29 (1H, dd, J=0.6, 8.1 Hz), 8.58 (1H, dd, J=2.1, 8.1 Hz), 9.19 (1H,dd, J=0.6, 2.1 Hz). 10.65 (1H, brs). 697

410 698

699

700

701

400 702

443

Text Example Assay of β-secretase-inhibiting Activity

Forty eight point five μL of substrate peptide solution(Biotin-XSEVNLDAEFRHDSGC-Eu: X=ε-amino-n-caponic acid, Eu=Europiumcryptate) was added to each well of 96-hole half-area plate (a blackplate: Corning Incorporated), and after addition of 0.5 d of the testsample (dissolved in N,N′-dimethylformaldehyde) and 1 μl of Recombinanthuman BACE-1(R&D Systems), the reaction mixture was incubated at 30° C.for 3 hours. The substrate peptide was synthesized by reacting CryptateTBPCOOH mono SMP (CIS bio international) with Biotin-XSEVNLDAEFRHDSGC(Peptide Institute, Inc.). The final concentrations of the substratepeptide and Recombinant human BACE-1 were adjusted to 18 nM and 7.4 nMrespectively, and the reaction was performed in sodium acetate buffer(50 mM sodium acetate, pH 5.0, 0.008% Triton X-10).

After the incubation for reaction, 50 μl of 8.0 μg/mlStreptavidin-XL665(CIS bio international) dissolved in phosphate buffer(150 mM K₂ HPO₄—KH₂PO₄, pH 7.0, 0.008% Triton X-100, 0.8 M KF) was addedto each well and left stand at 30° C. for an hour. After then,fluorescence intensity was measured (excitation wavelength: 320 nm,measuring wavelength: 620 nm and 665 min) using Wallac 1420 multilabelcounter (Perkin Elmer life sciences). Enzymatic activity was determinedfrom counting ratio of each wavelength (10,000×Count 665/Count 620) and50% inhibitory concentration against the enzymatic activity wascalculated. IC₅₀ values of the test compounds are indicated in Table139.

TABLE 139 Compound IC50 No. (uM) 3 0.08 11 0.17 12 0.16 26 4.85 34 0.1038 0.14 41 0.15 62 0.17 65 0.72 66 0.15 70 0.09 71 0.16 72 0.11 76 0.1880 0.07 86 0.19 87 0.09 92 0.08 93 0.08 94 0.17 101 0.08 105 0.13 1060.12 109 0.10 111 0.18 114 0.16 126 2.14 136 0.11 141 0.12 149 9.25 1502.48 151 6.77 155 5.96 163 6.79 164 0.08

Compound IC50 No. (μM) 461 0.03 464 0.43 468 0.02 473 0.17 478 0.08 4810.05 484 0.29 488 0.26 491 0.09 494 0.03 497 0.09 502 0.04 505 0.03 5080.04 514 0.24 517 0.13 521 0.18 526 0.41 530 0.09 537 0.02 542 0.02 5440.17 551 0.02 559 0.42 563 0.02 566 0.18 576 0.02 577 0.03 579 0.14 5800.13 585 0.06 589 0.06 591 0.10 593 0.28 594 0.17 597 0.07 598 0.03 5990.03 645 0.20

The following compounds have shown IC₅₀ values equal to or under 1 μM inthe same assay;

compounds 4, 5, 6, 8, 10, 18, 19, 20, 21, 22, 29, 32, 33, 35, 43, 45,46, 58, 59, 63, 64, 68, 69, 75, 77, 78, 79, 81, 82, 83, 84, 85, 88, 89,90, 91, 95, 96, 97, 98, 100, 102, 103, 104, 107, 108, 110, 112, 113,115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 127, 131, 132, 133,134, 135, 142, 143, 144, 145, 148, 152, 157, 158, 162 and 165.

Also, compounds 462, 463, 465, 467, 469, 470, 471, 472, 479, 482, 483,486, 489, 490, 492, 501, 503, 507, 508, 509, 510, 511, 512, 516, 518,519, 523, 527, 528, 529, 531, 532, 533, 536, 538, 539, 540, 542, 545,546, 547, 548, 549, 552, 553, 554, 555, 556, 557, 558, 560, 561, 562,564, 565, 567, 568, 569, 570, 571, 572, 573, 574, 575, 555, 556, 557,558, 560, 561, 562, 564, 565, 567, 568, 569, 570, 571, 572, 573, 574,575, 578, 581, 582, 583, 584, 586, 587, 590, 595, 596, 600, 601, 602,603, 604, 605, 606, 609, 612, 613, 637, 644, 646, 461, 468, 478, 491,502, 505, 508, 517, 530, 537, 542, 544, 559, 563, 566, 576, 577, 597,598, 599 and 645 showed IC₅₀ values equal to or under 1 μM in the sameassay.

Compound IC50 No. (μM) 652 0.06 655 0.01 660 0.11 662 0.17 664 0.02 6650.87 668 0.51 669 0.01 674 0.01 680 0.05 689 0.04 701 0.20 702 0.16

The following compounds also showed IC₅₀ values equal to or under 1 μMin the same assay;

compounds 647, 648, 649, 650, 651, 654, 656, 657, 658, 659, 661, 666,670, 671, 672, 673, 675, 676, 677, 678, 679, 683, 684, 685, 686, 687,688, 690, 691, 692, 693, 694, 695, 696 and 697, 652, 655, 660, 662, 664,665, 667, 669, 674 and 689.

Formulation Example 1

Granular formulation is prepared with the following ingredients;

Ingredient compound of the formula (I) 10 mg lactose 700 mg corn starch274 mg HPC-L 16 mg 1000 mg

Compound of the formula (I) and lactose are put through a sieve of No.60 mesh. Corn starch is put through a sieve of No. 120 mesh and theseare mixed with V-shaped mixer.

An aqueous solution of HPC-L (Hydroxypropyl cellulose of Low viscosity)is added to the mixed powder, kneaded, granulated (extrusiongranulation; pore diameter 0.5-1 mm) and put into a drying process. Theresulted dried granule is sieved with vibrating screen (12/60 mesh) togive a granular formulation.

Formulation Example 2

Granular formulation for capsule filling is prepared with the followingingredients;

Ingredient compound of the formula (I) 15 mg lactose 90 mg corn starch42 mg HPC-L 3 mg 150 mg

Compound of the formula (I) and lactose are put through a sieve of No.60 mesh. Corn starch is put through a sieve of No. 120 mesh and theseare mixed. An aqueous solution of HPC-L is added to the mixed powder,kneaded, granulated and dried. Particle size of the resulted driedgranule is regulated and each of 150 mg is filled in No. 5 hard-gelatincapsule.

Formulation Example 3

Tablet is prepared with the following ingredients;

Ingredient compound of the formula (I) 10 mg lactose 90 mgmicrocrystalline cellulose 30 mg CMC-Na 15 mg magnesium stearate 5 mg150 mg

Compound of the formula (I), lactose, microcrystalline cellulose andCMC—Na (sodium salt of carboxymethylcellulose) are put through a sieveof No. 60 mesh and mixed. Magnesium stearate is mixed with the mixedgranule above to give a mixed powder for tablet, which is compressed bya tabletting machine to give a tablet of 150 mg.

Formulation Example 4

The following ingredients were warmed, mixed and sterilized to give aninjection.

Ingredient compound of the formula (I) 3 mg non-ionic surfactant 15 mgpurified water for injection 1 ml

INDUSTRIAL APPLICABILITY

A compound of the present invention can be a useful drug for treatingdiseases induced by production, secretion and/or deposition of amyloid βprotein.

1. A compound of the formula (I):

wherein the ring A is phenyl or pyridyl, phenyl and pyridyl beingsubstituted optionally with at least one selected from the groupconsisting of (A) the substituent group α, the substituent group α beingat least one selected from the group consisting of halogen, hydroxy,lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl,acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, loweralkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio,carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl,sulfamoyl, lower alkylsulfamoyl, lower alkylsulfonyl, cyano, nitro, acarbocyclic group and a heterocyclic group; (B) lower alkyl optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, hydroxyimino and lower alkoxyimino; (C) amino loweralkyl substituted with one or more substituent(s) selected from thesubstituent group α; (D) hydroxyimino lower alkyl; (E) lower alkoxyiminolower alkyl; (F) lower alkenyl optionally substituted with one or moresubstituent(s) selected from the substituent group α; (G) lower alkynyloptionally substituted with one or more substituent(s) selected from thesubstituent group α; (H) lower alkoxy optionally substituted with one ormore substituent(s) selected from the substituent group α; (I) loweralkoxy lower alkoxy optionally substituted with one or moresubstituent(s) selected from the substituent group α; (J) loweralkenyloxy optionally substituted with one or more substituent(s)selected from the substituent group α; (K) lower alkoxy lower alkenyloxyoptionally substituted with one or more substituent(s) selected from thesubstituent group α; (L) lower alkynyloxy optionally substituted withone or more substituent(s) selected from the substituent group α; (M)lower alkoxy lower alkynyloxy optionally substituted with one or moresubstituent(s) selected from the substituent group α; (N) loweralkylthio optionally substituted with one or more substituent(s)selected from the substituent group α; (O) lower alkenylthio optionallysubstituted with one or more substituent(s) selected from thesubstituent group α; (P) lower alkynylthio optionally substituted withone or more substituent(s) selected from the substituent group α; (Q)lower alkylamino substituted with one or more substituent(s) selectedfrom the substituent group α; (R) lower alkenylamino substituted withone or more substituent(s) selected from the substituent group α; (S)lower alkynylamino substituted with one or more substituent(s) selectedfrom the substituent group α; (T) aminooxy optionally substituted withone or more substituent(s) selected from lower alkylidene and thesubstituent group α; (U) acyl substituted with one or moresubstituent(s) selected from the substituent group α; (V) loweralkylsulfonyl optionally substituted with one or more substituent(s)selected from the substituent group α; (W) lower alkylsulfinyloptionally substituted with one or more substituent(s) selected from thesubstituent group α; (X) sulfamoyl; (Y) lower alkylsulfamoyl optionallysubstituted with one or more substituent(s) selected from thesubstituent group α; (Z) a carbocyclic group optionally substituted withone or more substituent(s) selected from the substituent group α, azide,lower alkyl and halogeno lower alkyl; (AA) a heterocyclic groupoptionally substituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AB)carbocyclyl lower alkyl optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogeno lower alkyl; (AC) heterocyclyl lower alkyl optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AD)carbocyclyloxy optionally substituted with one or more substituent(s)selected from the substituent group α, azide, lower alkyl and halogenolower alkyl; (AE) heterocyclyloxy optionally substituted with one ormore substituent(s) selected from the substituent group α, azide, loweralkyl and halogeno lower alkyl; (AF) carbocyclyl lower alkoxy optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AG)heterocyclyl lower alkoxy optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogeno lower alkyl; (AH) carbocyclyl lower alkoxycarbonyloptionally substituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AI)heterocyclyl lower alkoxycarbonyl optionally substituted with one ormore substituent(s) selected from the substituent group α, azide, loweralkyl and halogeno lower alkyl; (AJ) carbocyclylthio optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AK)heterocyclylthio optionally substituted with one or more substituent(s)selected from the substituent group α, azide, lower alkyl and halogenolower alkyl; (AL) carbocyclyl amino optionally substituted with one ormore substituent(s) selected from the substituent group α, azide, loweralkyl and halogeno lower alkyl; (AM) heterocyclyl amino optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AN)carbocyclyl lower alkylamino optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogeno lower alkyl; (AO) heterocyclyl lower alkylamino optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AP)lower alkylsulfamoyl optionally substituted with one or moresubstituent(s) selected from the substituent group α; (AQ)carbocyclylsulfamoyl optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogeno lower alkyl; (AR) heterocyclylsulfamoyl optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AS)carbocyclylsulfonyl optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogeno lower alkyl; (AT) heterocyclylsulfonyl optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AU)carbocyclylcarbamoyl optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogeno lower alkyl; (AV) heterocyclyl carbamoyl optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AW)carbocyclyl lower alkylcarbamoyl optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogeno lower alkyl; (AX) heterocyclyl lower alkylcarbamoyloptionally substituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogeno lower alkyl; (AY)carbocyclyloxycarbonyl optionally substituted with one or moresubstituent(s) selected from the substituent group α, azide, lower alkyland halogen lower alkyl; (AZ) heterocyclyloxycarbonyl optionallysubstituted with one or more substituent(s) selected from thesubstituent group α, azide, lower alkyl and halogen lower alkyl; loweralkylenedioxy optionally substituted with halogen; (BA) oxo; (BB) azide;and (CC) one of the following formulae:

wherein Ak¹, Ak² and Ak³ are each independently a single bond,optionally substituted lower alkylene wherein the substituent(s) isselected from the substituent group α, optionally substituted loweralkenylene wherein the substituent(s) is selected from the substituentgroup α, or optionally substituted lower alkynylene wherein thesubstituent(s) is selected from the substituent group α; Ak⁴ isoptionally substituted lower alkylene wherein the substituent(s) isselected from the substituent group α, optionally substituted loweralkenylene wherein the substituent(s) is selected from the substituentgroup α, or optionally substituted lower alkynylene wherein thesubstituent(s) is selected from the substituent group α; W¹ and W³ areeach independently O or S, W² is O, S or NR⁵, R⁵ and R⁶ are eachindependently hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxylower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclyl lower alkyl,lower alkenyl, hydroxyl lower alkenyl, lower alkoxy lower alkenyl, loweralkoxycarbonyl lower alkenyl, carbocyclyl lower alkenyl, lower alkynyl,hydroxyl lower alkynyl, lower alkoxy lower alkynyl, lower alkoxycarbonyllower alkynyl, carbocyclyl lower alkynyl or acyl; R⁷ is hydrogen orlower alkyl; the ring B is a carbocyclic group or a heterocyclic group,the carbocyclic group and the heterocyclic group being substitutedoptionally with at least one selected from the above (A) to (BB) and pis 1 or 2; W¹, W³ or W⁵ may be independent when it is pluralized, R¹ isoptionally substituted lower alkyl wherein the substituent(s) isselected from the substituent group α, optionally substituted loweralkenyl wherein the substituent(s) is selected from the substituentgroup α, optionally substituted lower alkynyl wherein the substituent isselected from the substituent group α, an optionally substitutedcarbocyclic group wherein the substituent(s) is selected from a group oflower alkyl and the substituent group α, or an optionally substitutedheterocyclic group wherein the substituent(s) is selected from a groupof lower alkyl and the substituent group α, R^(2a) and R^(2b) are eachindependently hydrogen, optionally substituted lower alkyl wherein thesubstituent(s) is selected from the substituent group α or optionallysubstituted acyl wherein acyl includes aliphatic acyl, carbocyclylcarbonyl and heterocyclyl carbonyl, and the substituent(s) is selectedfrom the substituent group α, and the substituent(s) for a moiety of thering in carbocyclyl carbonyl and heterocyclylcarbonyl is selected from agroup of lower alkyl, the substituent group α and lower alkylsubstituted with one or more substituent(s) selected from thesubstituent group α, R^(3a), R^(3b), R^(3c) and R^(3d) are eachindependently hydrogen, halogen, hydroxy, optionally substituted loweralkyl wherein the substituent(s) is selected from the substituent groupα, optionally substituted lower alkenyl wherein the substituent(s) isselected from the substituent group α, optionally substituted acylwherein acyl includes aliphatic acyl, carbocyclyl carbonyl andheterocyclic carbonyl, and the substituent(s) is selected from thesubstituent group α, and the substituent(s) for a moiety of the ring incarbocyclyl carbonyl and heterocyclylcarbonyl is selected from a groupof lower alkyl, the substituent group α and lower alkyl substituted withone or more substituent(s) selected from the substituent group α,optionally substituted lower alkoxy wherein the substituent(s) isselected from the substituent group α, optionally substitutedcarbocyclyl lower alkyl wherein the substituent(s) is selected from thesubstituent group α, optionally substituted heterocyclyl lower alkylwherein the substituent(s) is selected from a group of lower alkyl andthe substituent group α, optionally substituted carbocyclyl lower alkoxywherein the substituent(s) is selected from a group of lower alkyl andthe substituent group α, optionally substituted heterocyclyl loweralkoxy wherein the substituent(s) is selected from a group of loweralkyl and the substituent group α, optionally substituted aralkylwherein the substituent(s) is selected from a group of lower alkyl andthe substituent group α, optionally substituted heteroaralkyl whereinthe substituent(s) is selected from a group of lower alkyl and thesubstituent group α, optionally substituted aralkyloxy wherein thesubstituent(s) is selected from a group of lower alkyl and thesubstituent group α, optionally substituted heteroaralkyloxy wherein thesubstituent(s) is selected from a group of lower alkyl and thesubstituent group α, optionally substituted lower alkylthio wherein thesubstituent(s) is selected from the substituent group α, carboxy,optionally substituted lower alkoxycarbonyl wherein the substituent(s)is selected from the substituent group α, optionally substituted aminowherein the substituent(s) is selected from a group of lower alkyl,acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic groupand a heterocyclic group, optionally substituted carbamoyl wherein thesubstituent(s) is selected from a group of lower alkyl, acyl, hydroxyl,lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and aheterocyclic group, an optionally substituted carbocyclic group whereinthe substituent(s) is selected from a group of lower alkyl and thesubstituent group α or an optionally substituted heterocyclic groupwherein the substituent(s) is selected from a group of lower alkyl andthe substituent group α, or R^(3a) and R^(3b) or R^(3c) and R^(3d) mayform a carbocyclic ring together with a linked carbon atom or may formoxo, provided the following compounds i) and ii) are excluded; i) acompound in which R^(2a) is hydrogen, R^(2b) is hydrogen, acetyl orphenyl, R¹ is methyl, and the ring A is phenyl or 4-methoxyphenyl; andii) a compound in which R^(2a) is hydrogen, R^(2b) is hydrogen, acetylor phenyl, R¹ is ethyl and the ring A is 3,4-dimethoxyphenyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein the ring A is

wherein the ring A′ is a carbocyclic group or a heterocyclic group, G is

wherein R⁵ is hydrogen, lower alkyl or acyl, R⁶ is optionallysubstituted lower alkyl which is substituted with one of more ofsubstituent(s) selected from the substituent group α, optionallysubstituted lower alkenyl which is substituted with one of more ofsubstituent(s) selected from the substituent group α or optionallysubstituted lower alkynyl which is substituted with one of more ofsubstituent(s) selected from the substituent group α, W¹ is O or S, W²is O, S or NR⁵, Ak is optionally substituted lower alkylene wherein thesubstituent(s) is selected from the substituent group α, optionallysubstituted lower alkenylene wherein the substituent(s) is selected fromthe substituent group α or optionally substituted lower alkynylenewherein the substituent(s) is selected from the substituent group α, thering B is a carbocyclic group or a heterocyclic group, the carbocyclicgroup and the heterocyclic group being substituted optionally with atleast one selected from the above (A) to (BB) and each R⁵ may beindependent: R⁴ is halogen, hydroxyl, mercapto, halogeno lower alkyl,lower alkoxy, amino, lower alkylamino, acylamino or lower alkylthio, nis an integer of 0 to 2, and each R⁴ may be independent; or apharmaceutically acceptable salt thereof.
 3. The compound of claim 2,wherein the ring A′ is phenyl or a nitrogen-containing aromaticheterocyclic group; or a pharmaceutically acceptable salt thereof. 4.The compound of claim 2, wherein the ring A′ is a nitrogen-containingaromatic monocyclic heterocyclic group; or a pharmaceutically acceptablesalt thereof.
 5. The compound of claim 1, wherein R¹ is C1-C3 alkyl; ora pharmaceutically acceptable salt thereof.
 6. The compound of claim 1,wherein both of R^(2a) and R^(2b) are hydrogen; or a pharmaceuticallyacceptable salt thereof.
 7. The compound of claim 1, wherein all ofR^(3a), R^(3b), R^(3c)and R^(3d) are hydrogen; or a pharmaceuticallyacceptable salt thereof.
 8. The compound of claim 1, wherein R^(3a) andR^(3b) are the same substituent selected from halogen and optionallysubstituted lower alkyl wherein the substituent(s) is selected from thesubstituent group α; or a pharmaceutically acceptable salt thereof. 9.The compound of claim 1, wherein R^(3c) and R^(3d) are the samesubstituent selected from halogen and optionally substituted lower alkylwherein the substituent(s) is selected from the substituent group α; ora pharmaceutically acceptable salt thereof.
 10. The compound of claim 1,wherein R^(3a) and R^(3b), or R^(3c) and R^(3d) form a carbocyclic ringtogether with a linked carbon atom; or a pharmaceutically acceptablesalt thereof.
 11. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable salt thereof as an activeingredient, and a pharmaceutically acceptable carrier.
 12. A method fortreating a condition selected from the group consisting of Down'sdisease, prion disease, mild cognitive impairment (MCI), Dutch-typehereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, degenerated dementia, vascular degenerated mixed dementia,dementia associated with Parkinson's disease, dementia associated withprogressive supranuclear paralysis, dementia associated withcorticobasal degeneration, diffuse Lewy Bodies Alzheimer's disease,age-related macular degeneration, Parkinson's disease, or amyloidangiopathy in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.